Nasal and Ophthalmic Delivery of Aqueous Corticosteroid Solutions

ABSTRACT

The present invention is directed to methods of treating nasal and/or ophthalmic diseases, symptoms, or disorders that are therapeutically responsive to corticosteroid therapy by delivering aqueous solution formulations comprising a corticosteroid to nasal and ophthalmic tissues. The invention is also directed to methods, systems, devices, and compositions for delivering aqueous solution formulations comprising a corticosteroid and an antihistamine to nasal and ophthalmic tissues.

RELATEDNESS OF THE APPLICATION

The subject application is a continuation-in-part of PCT/US2008/068872,which claims the benefit of priority from PCT/US07/72422, filed Jun. 29,2007, and PCT/US07/72387, filed Jun. 28, 2007. PCT/US07/72422 andPCT/US07/72387 claim the benefit of priority from U.S. Ser. No.11/479,979, filed Jun. 30, 2006, which is a continuation-in-part ofPCT/US05/00082, filed Dec. 31, 2004, now expired, which claims priorityunder 35 USC § 119 from U.S. Ser. No. 60/533,628, filed Dec. 31, 2003,now expired. All priority documents are incorporated herein in theirentirety by reference.

FIELD OF THE INVENTION

The present invention is directed to methods of treating nasal and/orophthalmic diseases, symptoms, or disorders that are therapeuticallyresponsive to corticosteroid therapy by delivering aqueous solutionformulations comprising a corticosteroid to nasal and ophthalmictissues. The invention is also directed to methods, systems, devices,and compositions for delivering aqueous solution formulations comprisinga corticosteroid and an antihistamine to nasal and ophthalmic tissues.

BACKGROUND OF THE INVENTION

The nasal administration of drugs allows for their deposition to thenose, sinuses, and other nasal cavities. Intranasal administration ofdrugs such as corticosteroids and antihistamines may be used to treatnasal symptoms including seasonal allergic rhinitis, perennial allergicrhinitis, perennial non-allergic rhinitis, nasal polyps, as well asprevention of post surgical polyps, chronic sinusitis, recurrentsinusitis, asthma, grass pollen rhinitis, hay fever, snoring, clusterheadache, and other diseases and disorders.

The ophthalmic administration of drugs allows for their deposition tothe eye, including the ocular mucosa, eye surface, cornea, conjuctiva,sclera, and posterior eye parts such as the retina, choroid, andvitreous and optic nerves, as well as tissues surrounding the eye.Ophthalmic administration of drugs such as corticosteroids andantihistamines may be used to treat ocular symptoms includingconjunctivitis, inflammation of tissue(s) in the eye, dry eye,filamentary keratitis, delayed tear clearance, pain, keratoconjunctivaldryness, keratoconjunctivitis sicca, lesions/tumors of the eye,infectious processes of the eye, bacterial infections, viral infections,glaucoma, uveitis, diabetic retinopathy, eye trauma, blepharitis,blepharoconjunctivitis, and other diseases or disorders.

Aqueous formulations containing a corticosteroid and a solubilizingagent have been prepared: Saidi et al. (U.S. Pat. No. 6,241,969); Kelleret al. (Respiratory Drug Delivery IX (2004) 221-231); Lintz et al. (AAPSAnnual Meeting and Exposition, Baltimore, Nov. 8, 2004; Poster M1128);Schueepp et al. (ATS 99^(th) International Conference, Seattle, May16-21, 2003; poster 1607); Russian Patent No. 2180217 to Chuchalin; U.S.Publication No. 2006/0045850; and Waldrep et al. (J. Aerosol Med.(1994), 7(2), 135-145); PCT International Publications No. WO 06/108556,No. WO 03/35030, and No. WO 06/37246 and European Publications No.EP1894559 and No. EP1712220 to PARI Pharma GmbH.

Cyclodextrins have been included in nasal or ophthalmic compositions:Kaur et al. (Curr. Drug Deliv. (2004), 1(4), 351-360); Shimpi et al.(Acta Pharm. (2005), 55(2), 139-56); Viegas et al. (U.S. Pat. No.6,136,334, No. 5,587,175, and No. 5,958,443); Pate et al. (U.S. Pat. No.5,977,180); Loftsson et al. (Acta Opthalmol. Scand. (2002), 80(2),144-50).

Underivatized and derivatized cyclodextrins can be used to prepareaqueous formulations containing a corticosteroid: U.S. Pat. No.5,376,645 and No. 5,134,127 to Stella et al.; U.S. Pat. No. 5,914,122 toOtterbeck et al.; Worth et al. (24^(th) International Symposium onControlled Release of Bioactive Materials (1997)); Kinnarinen et al.(11^(th) International Cyclodextrin Symposium CD, (2002)); U.S. Pat. No.5,472,954; U.S. Pat. No. 5,089,482; Zimmerer et al. in Respiratory DrugDelivery IX (2004) 461-464); Singh et al. (U.S. Pat. No. 7,128,928 andNo. 6,696,426); Loftsson (U.S. Pat. No. 7,115,586, U.S. Pat. No.5,472,954, and U.S. Pat. No. 5,324,718); Chang et al. (U.S. Pat. No.6,969,706); Beck et al. (U.S. Pat. No. 6,723,353 and No. 6,358,935);Buchanan et al. (U.S. Pat. No. 6,610,671); Pitha (U.S. Pat. No.6,576,261 and No. 5,935,941); Kis (U.S. Pat. No. 6,468,548); Müller etal. (U.S. Pat. No. 6,407,079); Wiebe et al. (U.S. Pat. No. 5,739,121);Guy (U.S. Pat. No. 5,576,311); Babcock et al. (U.S. Pat. No. 5,538,721);Folkman et al. (U.S. Pat. No. 5,227,372); Lipari (U.S. Pat. No.4,383,992); PCT International Publication No. WO 2004/087043 to SunPharmaceutical Industries Ltd.; Saari et al. (Graefes Arch. Clin. Exp.Opthalmol. (2006), 244(5), 620-6); Kristinsson et al. (Invest.Opthalmol. Vis. Sci. (1996), 37(6), 1199-203); Usayapant et al. (Pharm.Res. (1991), 8(12), 1495-9); Bary et al. (Eur. J. Pharm. Biopharm.(2000), 50(2), 237-244); U.S. Publication No. 2006/0193783; U.S.Publication No. 2002/0198174; European Publication No. EP 0435682; Lyonset al. (abstract in AAPS Annual Meeting and Exposition, Denver, Colo.USA, Oct. 1-25, 2001); Amselem et al. (U.S. Pat. No. 5,747,061).

Sulfoalkyl ether cyclodextrin derivatives can be used to prepare aqueousformulations containing a corticosteroid: U.S. Publication No.2007/0020336; U.S. Publication No. 2006/0120967; U.S. Publication No.2002/0150616 to Van de Cruys; U.S. Publications No. 20070249572, No.20070197487, No. 20070197486, No. 20070191599, No. 20070191327; No.20070191323, No. 20070185066, No. 20070178050, No. 20070178049, and No.20070160542 and PCT International Publications No. WO 07/95342, No. WO07/95341, No. WO 07/95339, No. WO 07/75963, No. WO 07/75859, No. WO07/75801, No. WO 07/75800, No. WO 07/75799, and No. WO 07/75798 to Hill;U.S. Publications No. 20070202054, No. 20070020299, No. 20070020298, andNo. 20070020196, and PCT International Publications No. WO 08/05692, No.WO 08/05691, No. WO 08/05053, No. WO 05/065651, No. WO 05/065649, No. WO05/065435 to Pipkin et al.; U.S. Publication No. 20060120967 and No.20060045850 to Namburi et al.; and U.S. Publications No. 2005085446 andNo. 20070049552 to Babu.

Corticosteroid-containing formulations for ophthalmic use have beendescribed: Pflugfelder et al. (U.S. Pat. No. 6,153,607), Sackeyfio etal. (U.S. Pat. No. 6,995,815), Guo et al. (U.S. Pat. Nos. 6,548,078 and6,217,895), Sher (U.S. Pat. No. 6,117,907), Clarke et al. (U.S. Pat.Nos. 5,358,943 and 4,945,089), Schwartz (U.S. Pat. Nos. 5,212,168 and4,904,649), and Saidi et al. (U.S. Pat. No. 6,241,969).

The nasal and/or ophthalmic delivery of an aqueous solution formulationcomprising a corticosteroid as a therapeutic agent alone or incombination with another therapeutic agent, such as an antihistamine,for the treatment of allergy-related disorders or symptoms would beuseful and especially desirable if it could provide an improved clinicalbenefit over the delivery of other formulations, such assuspension-based formulations.

SUMMARY OF THE INVENTION

The invention provides a method of treating, preventing or amelioratingin a subject a corticosteroid-responsive disease or disorder, meaning adisease or disorder in a subject that can be treated with atherapeutically effective amount of corticosteroid to provide a clinicalor therapeutic benefit to the subject. In some embodiments, thecorticosteroid-responsive disease or disorder is a disease, disorder,symptom, or condition of the nose or eye.

The invention provides a method for treating an allergic symptom ordisorder in a subject in need thereof, comprising:

nasally administering to the subject a corticosteroid solutioncomprising a therapeutically effective amount of a corticosteroid,SAE-CD, and a pharmaceutically acceptable aqueous liquid carrier,

wherein the corticosteroid solution provides more rapid relief from anallergic symptom or disorder compared to a corticosteroid suspension atthe same unit dose.

In some embodiments, the allergic symptom or disorder includes anon-nasal symptom selected from the group consisting of itchy/grittyeyes, tearing/watery eyes, red/burning eyes, itchy eyes and palate, andcombinations thereof.

The invention also provides a method for treating an ocular symptom ordisorder in a subject in need thereof, comprising:

nasally administering to the subject a corticosteroid solutioncomprising a therapeutically effective amount of a corticosteroid,SAE-CD, and a pharmaceutically acceptable aqueous liquid carrier,

wherein the ocular symptom or disorder is itchy/gritty eyes,tearing/watery eyes, red/burning eyes, or a combination thereof.

The invention also provides a system for treating an allergic symptom ordisorder in a subject in need thereof, comprising:

a corticosteroid solution comprising a therapeutically effective amountof a corticosteroid, a therapeutically effective amount of anantihistamine, SAE-CD, and a pharmaceutically acceptable aqueous liquidcarrier, and

a metered dose device for nasal administration of the corticosteroidsolution to the subject, wherein the corticosteroid solution is providedin the device.

In some embodiments, the system is for treating an ocular symptom ordisorder in a subject in need thereof.

The invention also provides a metered dose device for nasaladministration comprising a corticosteroid solution comprising atherapeutically effective amount of a corticosteroid, a therapeuticallyeffective amount of an antihistamine, SAE-CD, and a pharmaceuticallyacceptable aqueous liquid carrier.

In some embodiments, the invention provides a method for treating anasal symptom or disorder in a subject in need thereof, comprising:

nasally administering to the subject a corticosteroid solutioncomprising a therapeutically effective amount of a corticosteroid,SAE-CD, and a pharmaceutically acceptable aqueous liquid carrier,

wherein the nasal symptom or disorder is selected from the groupconsisting of: acute or chronic rhinitis, nasal polyps, post surgicalnasal polyps, snoring, cluster headache, and combinations thereof.

In some embodiments of the method for treating a nasal symptom ordisorder in a subject in need thereof, the symptom or disorder isinstead selected from the group consisting of obstructive sleep apnea,eustachian tube dysfunction, serous otitis media, sleep disturbances,daytime somnolesence, nasal furuncles, epistaxis, wounds of the nasal orsinunasal mucosa, dry nose syndrome, nasal bleeding, and combinationsthereof.

The invention also provides a method for treating an allergic symptom ordisorder in a subject in need thereof, comprising:

ophthalmically administering to the subject a corticosteroid solutioncomprising a therapeutically effective amount of a corticosteroid,SAE-CD, and a pharmaceutically acceptable aqueous liquid carrier,

wherein the corticosteroid solution provides more rapid relief from anallergic symptom or disorder compared to a corticosteroid suspension atthe same unit dose.

The invention also provides a method for treating ocular inflammation ina subject in need thereof, comprising:

ophthalmically administering to the subject a corticosteroid solutioncomprising a therapeutically effective amount of a corticosteroid,SAE-CD, and a pharmaceutically acceptable aqueous liquid carrier,

wherein the corticosteroid solution provides a more rapid reduction inocular inflammation compared with a corticosteroid suspension at thesame unit dose.

The invention also provides a system for treating an allergic symptom ordisorder in a subject in need thereof, comprising:

a corticosteroid solution comprising a therapeutically effective amountof a corticosteroid, a therapeutically effective amount of anantihistamine, SAE-CD, and a pharmaceutically acceptable aqueous liquidcarrier, and

a device for ophthalmic administration of the corticosteroid solution tothe subject, wherein the corticosteroid solution is provided in thedevice.

The invention also provides a device for ophthalmic administrationcomprising a corticosteroid solution comprising a therapeuticallyeffective amount of a corticosteroid, a therapeutically effective amountof an antihistamine, SAE-CD, and a pharmaceutically acceptable aqueousliquid carrier.

The administration device can be: 1) a metered dose device such as aatomizer, sprayer, pump spray, dropper, squeeze tube, squeeze bottle,pipette, ampule, nasal cannula, metered dose device, nasal sprayinhaler, nasal continuous positive air pressure device, or breathactuated bi-directional delivery device; or 2) a device for ophthalmicadministration such as a dropper, drop dispensing package, tube, eyespray device, or eye wash unit. The device can be adapted to to emit 10μl to 500 μl of corticosteroid solution per unit dose. The device canalso comprise a nozzle, wherein the nozzle comprises a valve, and thevalve provides a release of a volume of 25 μl to 260 μl per unit dosethrough the nozzle upon operation of the device.

In some embodiments, the corticosteroid is beclomethasone dipropionate,beclomethasone monopropionate, betamethasone, budesonide, ciclesonide,desisobutyryl-ciclesonide, dexamethasone, flunisolide, fluticasonepropionate, fluticasone furoate, mometasone furoate, triamcinoloneacetonide, or a combination thereof.

The invention also includes embodiments wherein the corticosteroidsolution further comprises one or more additional therapeuticallyeffective agents, such as an anti-IgE antibody, antibiotic agent,anticholinergic agent, antifungal agent, anti-inflammatory agent,anti-infective agent, antihistamine agent, analgesic agent,decongestant, expectorant, antitussive agent, antimicrobial agent,leukotriene receptor antagonist, or a combination thereof. Specificembodiments of these additional therapeutically effective agents can beselected from those disclosed herein or others suitable for nasal orophthalmic administration and for treatment of diseases, disorders orsymptoms of the nose or eye.

In some embodiments, the method further comprises administering atherapeutically effective amount of an antihistamine. In someembodiments, the antihistamine is diphenhydramine, clemastine,chlorpheniramine, brompheniramine, dexchlorpheniramine,dexbrompheniramine, triprolidine, doxylamine, tripelennamine, heptadine,carbinoaxime, bromdiphenhydramine, hydroxyzine, pyrilamine, acrivastine,AHR-11325, phenindamine, astemizole, azatadine, azelastine, cetirizine,ebastine, fexofenadine, ketotifen, Iodoxine, loratadine,descarboethoxyloratadine, levocabastine, mequitazine, oxatomide,setastine, tazifyline, temelastine, terfenadine, tripelennamine,terfenadine carboxylate, phenyltoloxamine, pheniramine, or a combinationthereof. In some embodiments, the antihistamine is carebastine,efletirizine, mapinastine, antazoline, bilastine, bepotastine besilate,rupatadine, emedastine, tecastemizole, epinastine, levocetirizine,mizolastine, noberastine, norastemizole, olopatadine, or a combinationthereof. In some embodiments the antihistamine is azelastine. In someembodiments, the antihistamine is azelastine, wherein the azelastine ispresent at an amount of about 30 μg to about 275 μg per unit dose. Insome embodiments, the antihistamine is azelastine, wherein theazelastine is present at a concentration of 0.5 to 10 mg/mL. In someembodiments, the antihistamine is olopatadine. In some embodiments, theantihistamine is azelastine, wherein the olopatadine is present at anamount of about 330 μg to about 2660 μg per unit dose. In someembodiments, the antihistamine is azelastine, wherein the olopatadine ispresent at a concentration of 1 to 15 mg/mL. In some embodiments, theantihistamine is cetirizine. In some embodiments, the antihistamine iscetirizine, wherein the cetirizine is present at an amount of about 0.25mg to about 4.4 mg per unit dose. In some embodiments, the antihistamineis cetirizine, wherein the cetirizine is present at a concentration of0.25 to 4.4 mg/mL.

In some embodiments, the administering of the corticosteroid solution isperformed once or twice daily.

In some embodiments, the allergic symptom or disorder is or furtherincludes a nasal symptom, non-nasal symptom, allergic rhinitis, seasonalallergic rhinitis, perennial allergic rhinitis, perennial non-allergicrhinitis, grass pollen rhinitis, have fever, nasal polyps, or acombination thereof. In some embodiments, the allergic symptom ordisorder is or further includes ocular symptom, bacterial rhinitis,fungal rhinitis, viral rhinitis, atrophic rhinitis, vasomotor rhinitis,blocked nose, nasal congestion, or a combination thereof.

In some embodiments, the nasal symptom is rhinorrhea, nasal congestion,nasal itchiness, sneezing, nasal obstruction, or a combination thereof.

In some embodiments, the non-nasal symptom is itchy/gritty eyes,tearing/watery eyes, red/burning eyes, itchy ears and palate, or acombination thereof.

In some embodiments, the corticosteroid is budesonide. In someembodiments, the corticosteroid is budesonide, wherein the budesonide ispresent at an amount of about 5 μg to about 500 μg per unit dose. Insome embodiments, the corticosteroid is budesonide, wherein thebudesonide is present at a concentration of 40 to 2000 μg/mL.

In some embodiments, the corticosteroid is fluticasone propionate.

In some embodiments, the corticosteroid is fluticasone furoate.

In some embodiments, the corticosteroid is mometasone furoate.

In some embodiments, the molar ratio of the SAE-CD to the corticosteroidis 1:1 or greater. In some embodiments, the molar ratio of the SAE-CD toan additional therapeutic agent is 1:1 or greater. In some embodiments,the molar ratio of the SAE-CD to an antihistamine is greater than 2:1.

Some embodiments of the invention includes those wherein thecorticosteroid solution comprises: 1) a corticosteroid, such asbudesonide, fluticasone propionate, fluticasone furoate, mometasonefuroate, ciclesonide, or a combination thereof; and 2) anothertherapeutically effective agent, such as azelastine, olopatadine,cetirizine, loratadine, desloratadine, azithromycin, voriconazole, or acombination thereof.

In some embodiments, the aqueous liquid carrier comprises water, buffer,alcohol, organic solvent, glycerin, propylene glycol, poly(ethyleneglycol), poloxamer, surfactant or a combination thereof. In someembodiments, the aqueous liquid carrier comprises povidone, polyol or acombination thereof.

Some embodiments of the invention also provide a unit dose of atherapeutic corticosteroid solution comprising: about 32 μg ofbudesonide; SAE-CD; pharmaceutically acceptable aqueous liquid carrier;disodium edetate of about 0.005 to about 0.1% by weight of the unitdose; and potassium sorbate of about 0.05 to about 0.2% by weight of theunit dose, and wherein the corticosteroid solution is suitable for nasaladministration to a subject in need thereof.

Some embodiments of the invention also provide a method of treatingpreventing or ameliorating in a subject a corticosteroid-responsivedisease or disorder, the method comprising metering into the nose of thesubject a therapeutically effective amount of budesonide that is lessthan about 320 μg per day, delivered as 8 or more unit doses, whereineach unit dose consists of about 32 μg of budesonide; SAE-CD; disodiumedetate of about 0.005 to about 0.1% by weight of the unit dose;potassium sorbate of about 0.05 to about 0.2% by weight of the unitdose; and a pharmaceutically acceptable aqueous liquid carrier.

In some embodiments, the corticosteroid solution has a pH of about 3.5to about 5 or about 4.2 to about 4.6.

In some embodiments, the SAE-CD is a compound, or mixture of compounds,of the Formula 1:

wherein:

-   n is 4, 5 or 6;-   R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈ and R₉ are each, independently, —O—    or a-O—(C₂-C₆ alkylene)-SO₃ ⁻ group, wherein at least one of R₁-R₉    is independently a —O—(C₂-C₆ alkylene)-SO₃ ⁻ group, a    —O—(CH₂)_(m)SO₃ ⁻ group wherein m is 2 to 6, —OCH₂CH₂CH₂SO₃ ⁻, or    —OCH₂CH₂CH₂CH₂SO₃ ⁻); and-   S₁, S₂, S₃, S₄, S₅, S₆, S₇, S₈ and S₉ are each, independently, a    pharmaceutically acceptable cation.

In some embodiments, the corticosteroid solution further comprises oneor more pharmaceutically acceptable excipients, such as a preservative,an antioxidant, a buffering agent, an acidifying agent, an alkalizingagent, a solubility-enhancing agent, a complexation-enhancing agent, adiluent, an electrolyte, glucose, a stabilizer, a bulking agent, anantifoaming agent, an oil, an emulsifying agent, flavor, sweetener, ataste-masking agent, a tonicity modifier, a surface tension modifier, aviscosity modifier, a density modifier, or a combination thereof.

In some embodiments, the SAE-CD is present at a concentration of about10 to about 500 mg/mL of corticosteroid solution, and/or the SAE-CD ispresent in an amount of 100 μg to 1000 mg per unit dose.

The invention includes all combinations of the embodiments and aspectsdisclosed herein. Accordingly, the invention includes the embodimentsand aspects specifically disclosed, broadly disclosed, or narrowlydisclosed herein, as well as combinations thereof and subcombinations ofthe individual elements of said embodiments and aspects.

These and other aspects of this invention will be apparent uponreference to the following detailed description, examples, claims andattached figures.

BRIEF DESCRIPTION OF THE FIGURES

The following drawings are given by way of illustration only, and thusare not intended to limit the scope of the present invention.

FIG. 1A depicts a phase solubility graph of the concentration (molar) ofcyclodextrin versus the concentration (molar) of budesonide for γ-CD,HP-β-CD and SBE7-β-CD.

FIG. 1B depicts a phase solubility graph for budesonide concentration(M) versus cyclodextrin concentration (M) for various SBG-γ-CD speciesand CAPTISOL.

FIG. 2 depicts a phase solubility diagram for fluticasone propionate inthe presence of several different cyclodextrins.

FIG. 3 depicts a phase solubility diagram for mometasone furoate in thepresence of several different cyclodextrins.

FIG. 4 depicts a phase solubility diagram for esterified andnon-esterified fluticasone in the presence of SAE(5-6)-γ-CD.

FIG. 5 depicts a bar chart summarizing the aqueous solubility ofbeclomethasone dipropionate in the presence of various SAE-CDderivatives.

FIGS. 6A to 6I depict charts detailing the results of a clinical studyconducted according to Example 33.

FIG. 7 depicts a graphical summary of the study protocol of Example 33.

FIG. 8A depicts a chart the TNSS change from baseline with onset ofaction for the first three time points in the study of Example 33.

FIG. 8B depicts a chart the TNNSS change from baseline with onset ofaction for the first three time points in the study of Example 33.

FIGS. 9A-9C depict the results of the effect that the three solutions ofExample 33 have on the EEC-QOLQ as determined using the Quality of LifeQuestionnaire.

FIGS. 10A-10C depict charts of the pH rate profile for degradation ofazelastine in the presence or absence of SAE-CD at varying temperaturesand pH's: FIG. 10A-Azelastine pH Rate Profile Area % (25° C.), 0.5 mg/mLazelastine HCl in 3 mM citrate @ pH 4, 5, & 6; with and without 1.75%CAPTISOL, Stored in 25° C. Stability Chamber; FIG. 10B—Azelastine pHRate Profile Area % (40° C.), 0.5 mg/mL azelastine HCl in 3 mM citrate @pH 4, 5, & 6; with and without 1.75% CAPTISOL, Stored in 40° C.Stability Chamber; FIG. 10C—Azelastine pH Rate Profile Area % (60° C.),0.5 mg/mL azelastine HCl in 3 mM citrate @ pH 4, 5, & 6; with andwithout 1.75% CAPTISOL, Stored in 60° C. Stability Chamber.

FIGS. 11A and 11B depict phase solubility diagrams for budesonide in thepresence of varying amounts of azelastine hydrochloride and fixedamounts of SBE-β-CD or SBE-γ-CD.

FIGS. 12A-12C depict charts for the change in baseline in the TNSS,TOSS, and TSS, respectively, in the study of Example 34 using CAPTISOLBudesonide+Azelastine solution, and budesonide and azelastine.

FIGS. 12D-12H depict charts of summaries for individual symptom scoresas described in Example 34.

FIG. 12I depicts the AUC in change from baseline for a number ofsymptoms measured in the study of Example 34.

FIGS. 12J-12L depict charts relating to a meta-analysis of the clinicalstudies of Examples 33 and 34.

FIGS. 13A-13B depict charts detailing the changes in ocular pressure ofrabbits treated according to Example 41.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to methods of treating nasal and/orophthalmic diseases, symptoms, or disorders that are therapeuticallyresponsive to corticosteroid therapy by delivering aqueous solutionformulations comprising a corticosteroid to nasal and ophthalmictissues. The invention is also directed to methods, systems, devices,and compositions for delivering aqueous solution formulations comprisinga corticosteroid and an antihistamine to nasal and ophthalmic tissues.The systems of the invention comprise an administration device, and acomposition of the invention. The composition of the invention is acorticosteroid solution comprising a corticosteroid and SAE-CD. Thecomposition can be a nasal or non-nasal composition or an ophthalmiccomposition. In some embodiments, a non-nasal composition excludes aninhalable composition for pulmonary delivery.

By including SAE-CD in a liquid composition containing corticosteroid,the corticosteroid is dissolved. The corticosteroid exhibits greaterstability in the presence of SAE-CD than it does in its absence. When asecond active agent is present, the second active agent can also exhibitgreater stability in the presence of SAE-CD than it does in its absence.

The methods, systems, devices, and compositions of the invention canprovide an enhanced pharmacokinetic profile over a suspensionformulation comprising approximately the same amount of a therapeuticagent and delivered under substantially the same conditions. Thetherapeutic agent is a corticosteroid alone or a corticosteroid combinedwith one or more additional therapeutic agents. As such, one or moretherapeutic agents in the methods, systems, devices, and compositions ofthe invention can demonstrate an enhanced pharmacokinetic profile whencompared with the same therapeutic agent or agents in a suspensionformulation. The term “enhanced pharmacokinetic profile” is taken tomean a higher AUC (e.g. AUC_(last) or AUC_((0→∞))) per μg of therapeuticagent delivered or administered, a higher Cmax per μg of therapeuticagent delivered or administered, increased bioavailability, absorptionor distribution of the therapeutic agent at the site of delivery, ashorter Tmax, or a longer Tmax. The methods, systems, devices, andcompositions of the invention can also provide other enhancements over asuspension-based formulation, such as enhanced drug delivery, increasedrate of drug administration, reduced treatment time, reduced toxicity,improved stability, enhanced bioabsorption, increased output rate,increased total output, reduced side effects associated with thetherapeutic agent, increased nasal cavity deposition, increasedparanasal sinus cavity deposition, increased ocular deposition, improvedquality of life, reduced mucociliary clearance, reduced ocularclearance, and/or improved patient compliance.

Alternatively, the methods, systems, devices, and compositions of theinvention provide substantially the same pharmacokinetic profile or anenhanced pharmacokinetic profile over a suspension formulationcomprising a higher amount of therapeutic agent and delivered undersubstantially the same conditions. The therapeutic agent in theformulation can be present at a dose that is less than about 80%, lessthan about 70%, less than about 60% less than about 50%, less than about40%, less than about 20%, or less than about 10% of that in thesuspension.

The amount and/or concentration of SAE-CD in the composition can bevaried as needed or as described herein to provide a composition thatpossesses a desired physical property, provide therapeutic effectivenessin subjects to which the composition is administered, and/or achieve adesired performance in an administration device. SAE-CD can be presentin an amount sufficient to solubilize and/or stabilize the therapeuticagent when the SAE-CD and therapeutic agent are placed in the aqueouscarrier. The aqueous carrier can be present in an amount sufficient toaid in dissolution of the therapeutic agent and form a solution ofsufficient volume and sufficiently low viscosity to permitadministration with an administration device. SAE-CD can be present insolid form or in solution in the aqueous carrier. The therapeutic agentcan be present in dry powder/particle form or in suspension in theaqueous carrier. In some embodiments, SAE-CD is present at aconcentration of about 10 to about 500 mg/mL of composition, and/orSAE-CD is present in an amount of 100 μg to 1000 mg per unit dose.

In some embodiments, SAE-CD is present in an amount sufficient todecrease the amount of unsolubilized therapeutic agent in thesuspension-based composition and to improve the administration of thesuspension-based composition. In some embodiments, SAE-CD is present inan amount sufficient to solubilize enough therapeutic agent such thatthe suspension-based composition to which the SAE-CD was added isconverted to a solution, substantially clear solution (containing lessthan 5% precipitate or solid), or a clear solution. It is possible thatother components of the suspension-based composition will not completelydissolve in, or may separate out from, the solution.

In some embodiments, SAE-CD is present in an amount sufficient tosolubilize at least 50%, at least 75%, at least 90%, at least 95% orsubstantially all of the therapeutic agent. Some embodiments of theinvention include those wherein at least 50% wt., at least 75% wt., atleast 90% wt., at least 95% wt., at least 98% wt., or all of thetherapeutic agent is dissolved in the liquid composition.

The compositions of the inventions are suitable for nasal and/orophthalmic administration. The compositions can be administered via anadministration device suitable for nasal administration or ophthalmicadministration of pharmaceutical compositions. As used herein, anadministration device is any pharmaceutically acceptable device adaptedto deliver a composition of the invention to a subject's nose or eye(s).A nasal administration device can be a metered administration device(metered volume, metered dose, or metered-weight) or a continuous (orsubstantially continuous) aerosol-producing device. Suitable nasaladministration devices also include devices that can be adapted ormodified for nasal administration. An ophthalmic administration devicecan be a dropper, drop dispensing package, tube, eye spray device, eyewash unit, and other devices known to those of ordinary skill in theart. In some embodiments, the nasally or ophthalmically administereddose can be absorbed into the bloodstream of a subject.

A metered nasal administration device delivers a fixed (metered) volumeor amount (dose) of a nasal composition upon each actuation. Exemplarymetered dose devices for nasal administration include, by way of exampleand without limitation, an atomizer, sprayer, dropper, squeeze tube,squeeze-type spray bottle, pipette, ampule, nasal cannula, metered dosedevice, nasal spray inhaler, breath actuated bi-directional deliverydevice, pump spray, pre-compression metered dose spray pump, monospraypump, bispray pump, and pressurized metered dose device. Theadministration device can be a single-dose disposable device,single-dose reusable device, multi-dose disposable device or multi-dosereusable device.

The compositions of the invention can be used with any known meteredadministration device. In some embodiments, the device is a pump nasalspray or a squeeze bottle. The performance of a composition of theinvention in a metered administration device is detailed in Example 35.

A continuous aerosol-producing device delivers a mist or aerosolcomprising droplet of a nasal composition dispersed in a continuous gasphase (such as air). A nebulizer, pulsating aerosol nebulizer, and anasal continuous positive air pressure device are exemplary of such adevice. Suitable nebulizers include, by way of example and withoutlimitation, an air driven jet nebulizer, ultrasonic nebulizer, capillarynebulizer, electromagnetic nebulizer, pulsating membrane nebulizer,pulsating plate (disc) nebulizer, pulsating/vibrating mesh nebulizer,vibrating plate nebulizer, a nebulizer comprising a vibration generatorand an aqueous chamber, a nebulizer comprising a nozzle array, andnebulizers that extrude a liquid formulation through a self-containednozzle array.

Commercially available administration devices that are used or can beadapted for nasal administration of a composition of the inventioninclude the AERONEB™ (Aerogen, San Francisco, Calif.), AERONEB GO(Aerogen); PARI LC PLUS™, PARI BOY™ N, PARI eflow (a nebulizer disclosedin U.S. Pat. No. 6,962,151), PARI LC SINUS, PARI SINUSTAR™, PARISINUNEB, VibrENT™ and PARI DURANEB™ (PARI Respiratory Equipment, Inc.,Monterey, Calif. or Munich, Germany); MICROAIR™ (Omron Healthcare, Inc,Vernon Hills, Ill.), HALOLITE™ (Profile Therapeutics Inc, Boston,Mass.), RESPIMAT™ (Boehringer Ingelheim Ingelheim, Germany) AERODOSE™(Aerogen, Inc, Mountain View, Calif.), OMRON ELITE™ (Omron Healthcare,Inc, Vernon Hills, Ill.), OMRON MICROAIR™ (Omron Healthcare, Inc, VernonHills, Ill.), MABISMIST™ II (Mabis Healthcare, Inc, Lake Forest, Ill.),LUMISCOPE™ 6610, (The Lumiscope Company, Inc, East Brunswick, N.J.),AIRSEP MYSTIQUE™, (AirSep Corporation, Buffalo, N.Y.), ACORN-1 andACORN-II (Vital Signs, Inc, Totowa, N.J.), AQUATOWER™ (MedicalIndustries America, Adel, Iowa), AVA-NEB (Hudson Respiratory CareIncorporated, Temecula, Calif.), AEROCURRENT™ utilizing the AEROCELL™disposable cartridge (AerovectRx Corporation, Atlanta, Ga.), CIRRUS(Intersurgical Incorporated, Liverpool, N.Y.), DART (ProfessionalMedical Products, Greenwood, S.C.), DEVILBISS™ PULMO AIDE (DeVilbissCorp; Somerset, Pa.), DOWNDRAFT™ (Marquest, Englewood, Colo.), FAN JET(Marquest, Englewood, Colo.), MB-5 (Mefar, Bovezzo, Italy), MISTY NEB™(Baxter, Valencia, Calif.), SALTER 8900 (Salter Labs, Arvin, Calif.),SIDESTREAM™ (Medic-Aid, Sussex, UK), UPDRAFT-II™ (Hudson RespiratoryCare; Temecula, Calif.), WHISPER JET ™ (Marquest Medical Products,Englewood, Colo.), AIOLOS™ (Aiolos Medicnnsk Teknik, Karlstad, Sweden),INSPIRON™ (Intertech Resources, Inc., Bannockburn, Ill.), OPTIMIST™(Unomedical Inc., McAllen, Tex.), PRODOMO™, SPIRA™ (Respiratory CareCenter, Hameenlinna, Finland), AERx™ Essence™ and Ultra™, (AradigmCorporation, Hayward, Calif.), SONIK™ LDI Nebulizer (Evit Labs,Sacramento, Calif.), ACCUSPRAY™ (BD Medical, Franklin Lake, N.J.),ViaNase ID ™ (electronic atomizer; Kurve, Bothell, Wash.), OptiMistdevice or OPTINOSE (Oslo, Norway), MAD Nasal (Wolfe Tory Medical, Inc.,Salt Lake City, Utah), Freepod™ (Valois, Marly le Roi, France), Dolphin™(Valois), Monopowder™ (Valois), Equadel™ (Valois), VP3™ and VP7™(Valois), VP6 Pump™ (Valois), Standard Systems Pumps (Ing. ErichPfeiffer, Radolfzell, Germany), AmPump (Ing. Erich Pfeiffer), CountingPump (Ing. Erich Pfeiffer), Advanced Preservative Free System (Ing.Erich Pfeiffer), Unit Dose System (Ing. Erich Pfeiffer), Bidose System(Ing. Erich Pfeiffer), Bidose Powder System (Ing. Erich Pfeiffer), SinusScience™ (Aerosol Science Laboratories, Inc., Camarillo, Calif.),ChiSys® (Archimedes, Reading, UK), Fit-Lizer® (Bioactis, Ltd, an SNBLsubsidiary (Tokyo, J P), Swordfish V™ (Mystic Pharmaceuticals, Austin,Tex.), DirectHaler™ Nasal (DirectHaler, Copenhagen, Denmark) andSWIRLER® Radioaerosol System (AMICI, Inc., Spring City, Pa.).

Particularly suitable administration devices include single dose andmulti-dose embodiments of: a pump spray bottle; the PARI eFlow (anebulizer equipped with a vibrating mesh nebulizer comprising avibration generator, an aerosol chamber, an inhalation valve, and anexhalation valve; U.S. Pat. No. 5,954,047, U.S. Pat. No. 6,026,808, U.S.Pat. No. 6,095,141, and U.S. Pat. No. 6,527,151, the entire disclosuresof which are hereby incorporated by reference); AERx Essence and AERxUltra (from ARADIGM; an aerosol generator comprising a nozzle array,whereby a liquid formulation is extruded through a self-contained nozzlearray); Aeroneb Go (a nebulizer equipped with a vibrating mesh nebulizercomprising a vibration generator, an aerosol chamber, an inlet and anoutlet); VibrENT™ (a nebulizer that delivers a pressure-pulsed aerosol;the delivery rate of liquid composition is about 0.160 mL/min; in PCTInternational Publications No. WP 2004/20029 and No. WO 2001/34232;Schuschnig et al. in European Patent Publication No. EP 1820493, andRespiratory Drug Delivery (2008), the entire disclosures of which arehereby incorporated by reference); PARI SINUSTAR (a nebulizer adaptedfor nasal administration that delivers an aqueous liquid composition ata rate of about 0.18 mL/min); and the PARI SINUS (including PARI LCStar, PARI LL and PARI Sprint).

The Aradigm AERx delivery system, the AERx Essence and AERx Ultra, isparticularly suitable for use according to the invention, as it isrecognized in the art as providing controlled dose expression, controlof generated aerosol particle size, control of aerosol particle size,and management of the inspiration and delivery process (Farr et al.,Drug Delivery Technology May 2002 Vol. 2, No. 3, 42-44). For example,the PARI eFlow vibrating plate nebulizer is particularly suitable foruse according to the invention, as it is recognized in the art asproviding the above-mentioned desired performance parameters (Keller etal. (ATS 99^(th) International Conference, Seattle, May 16-21, 2003;poster 2727).

The parameters used to effect nebulization via an electronic nebulizer,such as flow rate, mesh membrane size, aerosol inhalation chamber size,mask size and materials, inlet and outlet valves, outflow tube, internalchannel plurality of air outputs communicating with the internalchamber, vibration generator and power source may be varied inaccordance with the principles of the present invention to maximizetheir use with different types of aqueous corticosteroid compositions.In some embodiments, substantially all of a dose (weight or volume) isdelivered in less than 1.5 minutes or continuously delivered over 1.5 to60 minutes.

Valves and actuators can be obtained from Bespak (Milton Keynes, UK).Actuators used in the administration device can be horizontal orvertical. The administration device can incorporate the Velocityjet™micropump. The administration devices can be equipped with differenttypes of baffles, valves, tubes, channels, reservoirs, mixing chambers,vortex chamber, particle dispersion chamber, nasal adapter, vibratingpulse and/or sound wave generator.

Nebulizers that nebulize liquid formulations containing no propellantare suitable for use with the compositions provided herein. Any of theseand other known nebulizers can be used to deliver the formulation of theinvention including but not limited to the following: nebulizersavailable from Pari GmbH (Starnberg, Germany), DeVilbiss Healthcare(Heston, Middlesex, UK), Healthdyne, Vital Signs, Baxter, Allied HealthCare, Invacare, Hudson, Omron, Bremed, AirSep, Luminscope, Medisana,Siemens, Aerogen, Mountain Medical, Aerosol Medical Ltd. (Colchester,Essex, UK), AFP Medical (Rugby, Warwickshire, UK), Bard Ltd.(Sunderland, UK), Carri-Med. Ltd. (Dorking, UK), Plaem Nuiva (Brescia,Italy), Henleys Medical Supplies (London, UK), Intersurgical (Berkshire,UK), Lifecare Hospital Supplies (Leies, UK), Medic-Aid Ltd. (WestSussex, UK), Medix Ltd. (Essex, UK), Sinclair Medical Ltd. (Surrey, UK),and many other companies. The AERx and RESPIMAT nebulizers are describedby D. E. Geller (Respir. Care (2002), 47 (12), 1392-1404), the entiredisclosure of which is incorporated by reference.

Nebulizers for use herein include, but are not limited to, jetnebulizers (optionally sold with compressors), ultrasonic nebulizers,vibrating membrane, vibrating mesh nebulizers, vibrating platenebulizers, vibrating cone nebulizer, and others. Exemplary jetnebulizers for use herein include Pari LC plus/ProNeb, Pari LCplus/ProNeb Turbo, Pari LC Plus/Dura Neb 1000 & 2000 Pari LCplus/Walkhaler, Pari LC plus/Pari Master, Pari LC star, Omron CompAir XLPortable Nebulizer System (NE-C18 and JetAir Disposable nebulizer),Omron compare Elite Compressor Nebulizer System (NE-C21 and Elite AirReusable Nebulizer, Pari LC Plus or Pari LC Star nebulizer with PronebUltra compressor, Pulomo-aide, Pulmo-aide LT, Pulmo-aide traveler,Invacare Passport, Inspiration Healthdyne 626, Pulmo-Neb Traverler,DeVilbiss 646, Whisper Jet, Acorn II, Misty-Neb, Allied aerosol, SchucoHome Care, Lexan Plasic Pocet Neb, SideStream Hand Held Neb, Mobil Mist,Up-Draft, Up-Draft II, T Up-Draft, ISO-NEB, Ava-Neb, Micro Mist, andPulmoMate. Exemplary ultrasonic nebulizers for use herein includeMicroAir, UltraAir, Siemens Ultra Nebulizer 145, CompAir, Pulmosonic,Scout, 5003 Ultrasonic Neb, 5110 Ultrasonic Neb, 5004 Desk UltrasonicNebulizer, Mystique Ultrasonic, Lumiscope's Ultrasonic Nebulizer,Medisana Ultrasonic Nebulizer, Microstat Ultrasonic Nebulizer, andMabismist Hand Held Ultrasonic Nebulizer. Other nebulizers for useherein include 5000 Electromagnetic Neb, 5001 Electromagnetic Neb 5002Rotary Piston Neb, Lumineb I Piston Nebulizer 5500, Aeroneb PortableNebulizer System, Aerodose™ Inhaler, and AeroEclipse Breath ActuatedNebulizer. Exemplary vibrating membrane, mesh or plate nebulizers aredescribed by R. Dhand (Respiratory Care, (December 2002), 47(12), p.1406-1418), the entire disclosure of which is hereby incorporated byreference.

The volume or amount of composition administered can vary according tothe intended delivery target and administration device used. The amountof active agent in a dose or unit dose can vary according to theintended delivery target and administration device used.

During operation of a nebulizer based system, the corticosteroid can bedelivered at a rate of at least about 20-50 μg/min, or 10-200 μg/min,wherein this range may increase or decrease according to theconcentration of corticosteroid in the composition in the administrationdevice.

The present invention provides SAE-CD based formulations, wherein theSAE-CD is a compound of the Formula 1:

wherein:

-   n is 4, 5 or 6;-   R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈ and R₉ are each, independently, —O—    or a —O—(C₂-C₆ alkylene)-SO₃ ⁻ group, wherein at least one of R₁ to    R₉ is independently a —O—(C₂-C₆ alkylene)-SO₃ ⁻ group, preferably a    —O—(CH₂)_(m)SO₃ ⁻ group, wherein m is 2 to 6, preferably 2 to 4,    (e.g. —OCH₂CH₂CH₂SO₃ ⁻ or —OCH₂CH₂CH₂CH₂SO₃ ⁻); and-   S₁, S₂, S₃, S₄, S₅, S₆, S₇, S₈ and S₉ are each, independently, a    pharmaceutically acceptable cation which includes, for example, H⁺,    alkali metals (e.g. Li⁺, Na⁺, K⁺), alkaline earth metals (e.g.,    Ca⁺², Mg⁺²), ammonium ions and amine cations such as the cations of    (C₁-C₆)-alkylamines, piperidine, pyrazine, (C₁-C₆)-alkanolamine and    (C₄-C₈)-cycloalkanolamine.

Exemplary embodiments of the SAE-CD derivative of the invention includederivatives of the Formula II (SAEx-α-CD), wherein “x” ranges from 1 to18; of the Formula III (SAEy-β-CD), wherein “y” ranges from 1 to 21; andof the Formula IV (SAEz-γ-CD), wherein “z” ranges from 1 to 24 such as:

SAEx-α-CD SAEy-β-CD SAEz-γ-CD Name SEEx-α-CD SEEy-β-CD SEEz-γ-CDSulfoethyl ether CD SPEx-α-CD SPEy-β-CD SPEz-γ-CD Sulfopropyl ether CDSBEx-α-CD SBEy-β-CD SBEz-γ-CD Sulfobutyl ether CD SptEx-α-CD SPtEy-β-CDSPtEz-γ-CD Sulfopentyl ether CD SHEx-α-CD SHEy-β-CD SHEz-γ-CD Sulfohexylether CD

“SAE” represents a sulfoalkyl ether substituent bound to a cyclodextrin.The values “x”, “y” and “z” represent the average degree of substitutionas defined herein in terms of the number of sulfoalkyl ether groups perCD molecule. Some suitable SAE-CD's include, for example, sulfobutylether 4-β-CD or sulfobutyl ether 7-β-CD, sulfobutyl ether 6-γ-CD,sulfobutyl ether 4-γ-CD, sulfobutyl ether 3 to 8-γ-CD, or a sulfobutylether 5-γ-CD, or a compound of the formula I or a mixture thereof.

The SAE-CD used is described in U.S. Pat. No. 5,376,645 and U.S. Pat.No. 5,134,127 to Stella et al, the entire disclosures of which arehereby incorporated by reference. U.S. Pat. No. 3,426,011 to Parmerteret al. discloses anionic cyclodextrin derivatives having sulfoalkylether substituents. Lammers et al. (Recl. Trav. Chim. Pays-Bas (1972),91(6), 733-742); Staerke (1971), 23(5), 167-171) and Qu et al. (J.Inclusion Phenom. Macro. Chem., (2002), 43, 213-221) disclose sulfoalkylether derivatized cyclodextrins. U.S. Pat. No. 6,153,746 to Shah et al.discloses a process for the preparation of sulfoalkyl ether cyclodextrinderivatives. An SAE-CD can be made according to the disclosures ofStella et al., Parmerter et al., Lammers et al. or Qu et al., and ifprocessed to remove the major portion (>50%) of the underivatized parentcyclodextrin, used according to the present invention. The SAE-CD cancontain from 0% to less than 50% wt. of underivatized parentcyclodextrin.

The terms “alkylene” and “alkyl,” as used herein (e.g., in the-0-(C₂-C₆-alkylene)SO₃ ⁻ group or in the alkylamines), include linear,cyclic, and branched, saturated and unsaturated (i.e., containing onedouble bond) divalent alkylene groups and monovalent alkyl groups,respectively. The term “alkanol” in this text likewise includes bothlinear, cyclic and branched, saturated and unsaturated alkyl componentsof the alkanol groups, in which the hydroxyl groups can be situated atany position on the alkyl moiety. The term “cycloalkanol” includesunsubstituted or substituted (e.g., by methyl or ethyl)cyclic alcohols.

In some embodiments of the present invention, compositions contain amixture of cyclodextrin derivatives, having the structure set out informula (I), where the composition overall contains on the average atleast 1 and up to 3n+6 alkylsulfonic acid moieties per cyclodextrinmolecule. The present invention also provides compositions containing asingle type of cyclodextrin derivative, or at least 50% of a single typeof cyclodextrin derivative. The invention also includes formulationscontaining cyclodextrin derivatives having a narrow or wide and high orlow degree of substitution. These combinations can be optimized asneeded to provide cyclodextrins having particular properties.

The present invention also provides compositions containing a mixture ofcyclodextrin derivatives wherein two or more different types ofcyclodextrin derivatives are included in the composition. By differenttypes, is meant cyclodextrins derivatized with different types offunctional groups e.g., hydroxyalkyl and sulfoalkyl. Each independentdifferent type can contain one or more functional groups, e.g. SBE-CDwhere the cyclodextrin ring has only sulfobutyl functional groups, andhydroxypropyl-ethyl-β-CD where the cyclodextrin ring has bothhydroxypropyl functional groups and ethyl functional groups. The amountof each type of cyclodextrin derivative present can be varied as desiredto provide a mixture having the desired properties.

Exemplary SAE-CD derivatives include SBE4-β-CD, SBE7-β-CD, SBE11-β-CD,SBE3.4-γ-CD, SBE4.2-γ-CD, SBE4.9-γ-CD, SBE5.2-γ-CD, SBE6.1-γ-CD,SBE7.5-γ-CD, SBE7.8-γ-CD and SBE5-γ-CD which correspond to SAE-CDderivatives of the formula I wherein n=5, 5, 5 and 6; m is 4; and thereare on average 4, 7, 11 and 5 sulfoalkyl ether substituents present,respectively. These SAE-CD derivatives increase the solubility of poorlywater soluble active agents to varying degrees.

Since SAE-CD is a poly-anionic cyclodextrin, it can be provided indifferent salt forms. Suitable counterions include cationic organicatoms or molecules and cationic inorganic atoms or molecules. The SAE-CDcan include a single type of counterion or a mixture of differentcounterions. The properties of the SAE-CD can be modified by changingthe identity of the counterion present. For example, a first salt formof SAE-CD can have a greater corticosteroid stabilizing and/orsolubilizing power than a different second salt form of SAE-CD.Likewise, an SAE-CD having a first degree of substitution can have agreater corticosteroid stabilizing and/or solubilizing power than asecond SAE-CD having a different degree of substitution.

The liquid compositions and systems of the invention provide an improvedclinical benefit or therapeutic benefit over an otherwise similarsuspension-based formulations excluding SAE-CD but comprisingsubstantially the same dose of active agent, such as corticosteroid.Exemplary advantages may include enhanced drug delivery, increased rateof drug administration, reduced treatment time, reduced toxicity, easeof manufacture, assurance of sterility, improved stability, enhancedbioabsorption, no concern for solid particle growth, enhancedpharmacokinetic profile, reduced corticosteroid-related side effects,improved patient quality of life, and/or improved clinical orpharmaceutical performance over the suspension formulation.

The enhanced solubilization of a corticosteroid by one SAE-CD versusanother is demonstrated by the data in the following tables which depictthe molar solubility for fluticasone propionate with different SAE-CDsat about 0.03 to 0.12M concentrations such that the solubilizing powerfollowed about this rank order over this concentration range of SAE-CD:SBE5.2-γ-CD>SPE5.4-γ-CD>SBE6.1-γ-CD>SBE9.7-γ-CD>>SBE7-α-CD >SBE6.7-β-CD>SPE7-β-CD.For mometasone furoate, the solubilizing power followed about this rankorder over this concentration range of SAE-CD:SBE9.7-γ-CD>SBE6.1-γ-CD>SBE5.2-γ-CD>>SPE5.4-γ-CD>SBE7-α-CD>SBE6.7-β-CD>SPE7-β-CD.Differences were also observed for the binding of budesonide (andtriamcinolone with specific embodiments of SAE-CD. According to theinvention, a SAE-γ-CD binds a corticosteroid better than a SAE-β-CDdoes. Also, a SAE-β-CD binds budesonide better than a SAE-α-CD does. Thephase solubility data is summarized in Example 23 and FIGS. 2-3.

The inventors have also discovered that SAE-γ-CD is particularlysuitable for use in complexing esterified and non-esterifiedcorticosteroids as compared to complexation of the same corticosteroidswith SAE-β-CD or SAE-α-CD. The table in Example 23 summarizes the phasesolubility data depicted in FIG. 4 for fluticasone and fluticasonepropionate with various different SAE-γ-CD species having a degree ofsubstitution in the range of 5-10.

SAE-γ-CD is more effective at binding with a particular regioisomer ofesterified corticosteroids than is SAE-β-CD or SAE-α-CD. The procedureset forth in Example 18 details the comparative evaluation of thebinding of SAE-γ-CD and SAE-β-CD with a series of structurally relatedcorticosteroid derivatives.

By “complexed” is meant “being part of a clathrate or inclusion complexwith”, i.e., a complexed therapeutic agent is part of a clathrate orinclusion complex with a cyclodextrin derivative. By “major portion” ismeant at least about 50% by weight. Thus, a formulation according to thepresent invention can contain an active agent of which more than about50% by weight is complexed with a cyclodextrin. The actual percent ofactive agent that is complexed will vary according to the complexationequilibrium binding constant characterizing the complexation of aspecific cyclodextrin to a specific active agent. The invention alsoincludes embodiments wherein the active agent is not complexed with thecyclodextrin or wherein a minor portion of the active agent is complexedwith the derivatized cyclodextrin. It should be noted that an SAE-CD, orany other anionic derivatized cyclodextrin, can form one or more ionicbonds with a positively charged compound. This ionic association canoccur regardless of whether the positively charged compound is complexedwith the cyclodextrin either by inclusion in the cavity or formation ofa salt bridge.

The binding of a drug to the derivatized cyclodextrin can be improved byincluding an acid or base along with the drug and cyclodextrin. Forexample, the binding of a basic drug with the cyclodextrin might beimproved by including an acid along with the basic drug andcyclodextrin. Likewise, the binding of an acidic drug with thecyclodextrin might be improved by including a base (alkaline material)along with the acidic drug and cyclodextrin. The binding of a neutraldrug might be improved by including a basic, acidic or other neutralcompound along with the neutral drug and cyclodextrin. Suitable acidiccompounds include inorganic and organic acids. Examples of inorganicacids are mineral acids, such as hydrochloric and hydrobromic acid.Other suitable acids include sulfuric acid, sulfonic acid, sulfenicacid, and phosphoric acid. Examples of organic acids are aliphaticcarboxylic acids, such as acetic acid, ascorbic acid, carbonic acid,citric acid, butyric acid, fumaric acid, glutaric acid, glycolic acid,α-ketoglutaric acid, lactic acid, malic acid, mevalonic acid, maleicacid, malonic acid, oxalic acid, pimelic acid, propionic acid, succinicacid, tartaric acid, or tartronic acid. Aliphatic carboxylic acidsbearing one or more oxygenated substituents in the aliphatic chain arealso useful. A combination of acids can be used.

Suitable basic compounds include but are not limited to inorganic andorganic bases. Suitable inorganic bases include ammonia, metal oxide andmetal hydroxide. Suitable organic bases include primary amine, secondaryamine, tertiary amine, imidazole, triazole, tetrazole, pyrazole, indole,diethanolamine, triethanolamine, diethylamine, methylamine, tromethamine(TRIS), aromatic amine, unsaturated amine, primary thiol, and secondarythiol. A combination of bases can be used.

An anionic derivatized cyclodextrin can complex or otherwise bind withan acid-ionizable agent. As used herein, the term acid-ionizable agentis taken to mean any compound that becomes or is ionized in the presenceof an acid. An acid-ionizable agent comprises at least oneacid-ionizable functional group that becomes ionized when exposed toacid or when placed in an acidic medium. Exemplary acid-ionizablefunctional groups include a primary amine, secondary amine, tertiaryamine, quaternary amine, aromatic amine, unsaturated amine, primarythiol, secondary thiol, sulfonium, hydroxyl, enol and others known tothose of ordinary skill in the chemical arts.

The degree to which an acid-ionizable agent is bound by non-covalentionic binding versus inclusion complexation formation can be determinedspectrophotometrically using methods such as ¹HNMR, ¹³CNMR, or circulardichroism, for example, and by analysis of the phase solubility data forthe acid-ionizable agent and anionic derivatized cyclodextrin. Theartisan of ordinary skill in the art will be able to use theseconventional methods to approximate the amount of each type of bindingthat is occurring in solution to determine whether or not bindingbetween the species is occurring predominantly by non-covalent ionicbinding or inclusion complex formation. An acid-ionizable agent thatbinds to derivatized cyclodextrin by both means will generally exhibit abi-phasic phase solubility curve. Under conditions where non-covalentionic bonding predominates over inclusion complex formation, the amountof inclusion complex formation, measured by NMR or circular dichroism,will be reduced even though the phase solubility data indicatessignificant binding between the species under those conditions;moreover, the intrinsic solubility of the acid-ionizable agent, asdetermined from the phase solubility data, will generally be higher thanexpected under those conditions.

As used herein, the term non-covalent ionic bond refers to a bond formedbetween an anionic species and a cationic species. The bond isnon-covalent such that the two species together form a salt or ion pair.An anionic derivatized cyclodextrin provides the anionic species of theion pair and the acid-ionizable agent provides the cationic species ofthe ion pair. Since an anionic derivatized cyclodextrin is multi-valent,an SAE-CD can form an ion pair with one or more acid-ionizable agents.

The parent cyclodextrins have limited water solubility as compared toSAE-CD and HPCD. Underivatized α-CD has a water solubility of about14.5% w/v at saturation. Underivatized β-CD has a water solubility ofabout 1.85% w/v at saturation. Underivatized γ-CD has a water solubilityof about 23.2% w/v at saturation. Dimethyl-beta-cyclodextrin (DMCD)forms a 43% w/w aqueous solution at saturation. The SAE-CD can becombined with one or more other cyclodextrins or cyclodextrinderivatives in the composition to solubilize the corticosteroid.

Other water soluble cyclodextrin derivatives that can be used accordingto the invention include the hydroxyethyl, hydroxypropyl (including 2-and 3-hydroxypropyl) and dihydroxypropyl ethers, their correspondingmixed ethers and further mixed ethers with methyl or ethyl groups, suchas methylhydroxyethyl, ethyl-hydroxyethyl and ethyl-hydroxypropyl ethersof alpha-, beta- and gamma-cyclodextrin; and the maltosyl, glucosyl andmaltotriosyl derivatives of alpha, beta- and gamma-cyclodextrin, whichcan contain one or more sugar residues, e.g. glucosyl or diglucosyl,maltosyl or dimaltosyl, as well as various mixtures thereof, e.g. amixture of maltosyl and dimaltosyl derivatives. Specific cyclodextrinderivatives for use herein include hydroxypropyl-beta-cyclodextrin,hydroxyethyl-beta-cyclodextrin, hydroxypropyl-gamma-cyclodextrin,hydroxyethyl-gamma-cyclodextrin, dihydroxypropyl-beta-cyclodextrin,glucosyl-alpha-cyclodextrin, glucosyl-beta-cyclodextrin,diglucosyl-beta-cyclodextrin, maltosyl-alpha-cyclodextrin,maltosyl-beta-cyclodextrin, maltosyl-gamma-cyclodextrin,maltotriosyl-beta-cyclodextrin, maltotriosyl-gamma-cyclodextrin anddimaltosyl-beta-cyclodextrin, and mixtures thereof such asmaltosyl-beta-cyclodextrin/dimaltosyl-beta-cyclodextrin, as well asmethyl-beta-cyclodextrin. Procedures for preparing such cyclodextrinderivatives are well-known, for example, from Bodor U.S. Pat. No.5,024,998 dated Jun. 18, 1991, and references cited therein. Othercyclodextrins suitable for use in the present invention include thecarboxyalkyl thioether derivatives such as ORG 26054 and ORG 25969 madeby ORGANON (AKZO-NOBEL), hydroxybutenyl ether derivatives made byEASTMAN, sulfoalkyl-hydroxyalkyl ether derivatives, sulfoalkyl-alkylether derivatives, and other derivatives as described in US PregrantPatent Application Publications No. 2002/0128468, No. 2004/0106575, No.2004/0109888, and No. 2004/0063663, or U.S. Pat. No. 6,610,671, No.6,479,467, No. 6,660,804, or No. 6,509,323.

The HP-β-CD can be obtained from Research Diagnostics Inc. (Flanders,N.J.). HP-β-CD is available with different degrees of substitution.Exemplary products include ENCAPSIN™ (degree of substitution˜4;HP4-β-CD) and MOLECUSOL™ (degree of substitution˜8; HP8-β-CD); however,embodiments including other degrees of substitution are also available.Since HPCD is non-ionic, it is not available in salt form.

Dimethyl cyclodextrin is available from FLUKA Chemie (Buchs, CH) orWacker (Iowa). Other derivatized cyclodextrins suitable in the inventioninclude water soluble derivatized cyclodextrins. Exemplary water-solublederivatized cyclodextrins include carboxylated derivatives; sulfatedderivatives; alkylated derivatives; hydroxyalkylated derivatives;methylated derivatives; and carboxy-β-cyclodextrins, e.g.succinyl-β-cyclodextrin (SCD), and6^(A)-amino-6^(A)-deoxy-N-(3-carboxypropyl)-β-cyclodextrin. All of thesematerials can be made according to methods known in the prior art.Suitable derivatized cyclodextrins are disclosed in, e.g., ModifiedCyclodextrins: Scaffolds and Templates for Supramolecular Chemistry(Eds. Christopher J. Easton, Stephen F. Lincoln, Imperial College Press,London, UK, 1999) and New Trends in Cyclodextrins and Derivatives (Ed.Dominique Duchene, Editions de Santé, Paris, France, 1991).

Sulfobutyl ether β-cyclodextrin (CAPTISOL, CyDex Inc., degree ofsubstitution=6.6), 2-hydroxypropyl β-cyclodextrin (HP-β-CD, CERESTAR,degree of substitution=5.5), succinylated-β-cyclodextrin (S-CD,Cyclolab), and 2,6,di-o-methyl-β-cyclodextrin (DM-CD, Fluka) % w/wsolutions were prepared at their native pH or buffered as needed.Sulfoalkyl ether γ-CD and sulfoalkyl ether α-CD derivatives wereobtained from CyDex, Inc. (Lenexa, Kans.) and The University of Kansas(Lawrence, Kans.).

The amount of derivatized cyclodextrin required to provide the desiredeffect will vary according to the materials comprising the formulation.

Different cyclodextrins are able to solubilize a corticosteroid todifferent extents. FIG. 1A depicts a molar phase solubility curve forbudesonide with HP-β-CD, SBE7-β-CD, and γ-CD as compared to water. Theinventors have found that SAE-CD is superior to other cyclodextrins andcyclodextrin derivatives at solubilizing budesonide. On a molar basis,SBE-β-CD is a better solubilizer of budesonide than HP-β-CD. Inaddition, the solubilizing power among the SAE-CD derivatives followedabout this rank order for budesonide over a SAE-CD concentration rangeof 0.04 to 0.1 M:SBE5.2-γ-CD˜SPE5.4-γ-CD>SBE6.1-γ-CD>SBE7-α-CD>SBE9.7-γ-CD˜SBE6.7-β-CD>SPE7-β-CD.For example, a 0.1 M concentration of SBE7-β-CD was able to solubilize agreater amount of budesonide than either γ-CD or HP-β-CD. Moreover,SAE-CD-containing nebulizable formulations provide a greater output ratefor corticosteroid by nebulization as compared to γ-CD or HP-β-CDadministered under otherwise similar conditions. Additional phasesolubility data is depicted in FIG. 1B for various SBE-γ-CD derivatives(SBE4.9-γ-CD, SBE5.23-γ-CD, SBE6-γ-CD, SBE9.67-γ-CD, and SBE4.9-γ-CD)and CAPTISOL. The data indicate that the SBE-γ-CD derivatives generallyoutperform CAPTISOL in dissolution of budesonide.

The output rate (the rate at which the dose of the therapeuticallyeffective agent(s) in the corticosteroid solution is administered ordelivered) will vary according to the performance parameters of thedevice used to administer the dose. The higher the output rate of agiven device, the lower the amount of time required to deliver oradminister the corticosteroid solution, as defined herein, or the doseof the therapeutically effective agent(s) in the corticosteroidsolution.

Nebulization of CAPTISOL solutions provides several advantages withrespect to other cyclodextrins. The droplets leaving the nebulizer areof a more advantageous size and the CAPTISOL solutions are nebulizedfaster than similar solutions of other Cyclodextrins. The smallerdroplet size of aerosolized composition is favored for delivery ofactive agents such as a corticosteroid to the paranasal sinus cavitiesand/or deep nasal cavity.

CAPTISOL is emitted from a nebulizer faster and also to a greater extentthan the other cyclodextrins, thus the output rate of the nebulizer isgreater when CAPTISOL is nebulized. The output rate is highest for theCAPTISOL solution as compared to other cyclodextrin solutions indicatingthat an equivalent amount of drug can be delivered in a shorter periodof time. Under the conditions used, β-CD is unable to solubilize anequivalent amount of corticosteroid due to the limited solubility ofβ-CD in water.

The compositions of the invention can be made from othersuspension-based aqueous formulations, which formulations can be adaptedfor nasal delivery, by addition of SAE-CD thereto. Exemplarysuspension-based aqueous formulations include the UDB formulation(Sheffield Pharmaceuticals, Inc.), VANCENASE™ AQ (beclomethasonedipropionate aqueous suspension; Schering Corporation, Kenilworth,N.J.), ATOMASE™ (beclomethasone dipropionate aqueous suspension; DouglasPharmaceuticals Ltd., Aukland, Australia), BECONASE™ (beclomethasonedipropionate aqueous suspension; Glaxo Wellcome), NASACORT AQ™(triamcinolone acetonide nasal spray, Aventis Pharmaceuticals),TRI-NASAL™ (triamcinolone acetonide aqueous suspension; MuroPharmacaceuticals Inc.) and AEROBID-M™ (flunisolide inhalation aerosol,Forest Pharmaceuticals), NASALIDE™ and NASAREL™ (flunisolide nasalspray, Ivax Corporation), FLONASE™ (fluticasone propionate,GlaxoSmithKline), and NASONEX™ (mometasone furoate, Schering-PloughCorporation).

The suspension formulation can comprise corticosteroid present inparticulate, microparticulate, nanoparticulate or nanocrystalline form.Accordingly, an SAE-CD can be used to improve the administration of acorticosteroid suspension-based formulation. Moreover, the SAE-CDoutperforms other cyclodextrin derivatives.

In some embodiments, SAE-CD (in solid or liquid form) and asuspension-based formulation comprising corticosteroid are mixed. TheSAE-CD is present in an amount sufficient to increase the amount ofsolubilized corticosteroid, i.e. decrease the amount of unsolubilizedcorticosteroid, therein. Prior to administration, the liquid can beoptionally aseptically filtered or terminally sterilized. The liquid isthen nasally administered to a subject. As a result, the amount of drugthat the subject receives is higher than the subject would have receivedhad the unaltered suspension formulation been administered.

In some embodiments, SAE-CD (in liquid form, as ready-to-use liquid oras a concentrate) and a solid formulation comprising corticosteroid aremixed to form a liquid composition. The SAE-CD is present in an amountsufficient to solubilize a substantial portion of the corticosteroid.The liquid is then administered nasally or ophthalmically using asuitable administration device.

In other embodiments, SAE-CD (in solid form) and a solid formulationcomprising corticosteroid are mixed to form a solid mixture to which isadded an aqueous liquid carrier in an amount sufficient to form anebulizable formulation. Mixing and/or heating are optionally employedupon addition of the liquid carrier to form the formulation. The SAE-CDis present in an amount sufficient to solubilize a substantial portionof the corticosteroid. The formulation is then administered nasallyusing an administration device as defined herein.

In some embodiments, the nasal device is a nebulizer for nasaladministration. The size of the reservoir varies from one type ofnebulizer to another. The volume of the liquid formulation can beadjusted as needed to provide the required volume for loading into thereservoir of a particular type or brand of nebulizer. The volume can beadjusted by adding additional liquid carrier or additional solutioncontaining SAE-CD. In general, the reservoir volume of a nebulizer isabout 10 μl to 100 mL. Low volume nebulizers, such as ultrasonic andvibrating mesh/vibrating plate/vibrating cone/vibrating membranenebulizers, pre-filled reservoir strips inclusive of delivery nozzletypically have a reservoir volume of 10 μl to 6 mL or 10 μl to 5 mL. Thelow volume nebulizers provide the advantage of shorter administrationtimes as compared to large volume nebulizers.

Example 28 details a procedure for preparation of a solution of theinvention to be used with a low volume (low reservoir volume and/or lowreservoir residual volume) nebulizer, such as an AERx nebulizer. Thesolutions of the invention can be nebulized with any nebulizer; however,with an AERx delivery system that coordinates both the nasal inspirationand delivery processes to optimize deep paranasal sinus cavitypenetration, an initial sample volume of about 10 μl to 100 μl, or 50 μlcan be used to load AERx Strip multiple unit dose container.Administration of this solution with the system makes it feasible for atherapeutic dose to be administered to a subject in a single puff (asingle full nasal inspiration by a subject, i.e. 3-5 seconds) vianebulization. Based on general performance expectations of such devicesthe corticosteroid can be expected to be delivered to the nose in asingle dosing event using corticosteroid solutions prepared with SAECD.

Example 32 details a procedure for the comparison of nebulizationparameters in four different nebulizers using a formulation of theinvention and PULMICORT RESPULES (suspension-based formulation). In eachcase, the formulation of the invention out performs the suspension-basedformulation. The solution of the invention provide a 1.25, 1.4, 2.1,3.3, 3.67, 1.25 to 3.7, or 1.25 to 4 fold increase in the amount ofbudesonide delivered. Under the conditions tested, the AIRSEP MYSTIQUEwas most efficient at emitting/nebulizing the SAE-CD/budesonideformulation.

In some embodiments, a suspension-based formulation is converted to aliquid formulation prior to administration (as a mist or aerosol) to asubject. The conversion can take place in the same container in whichthe suspension is provided, in a different container, or in thereservoir of an administration device. In order to form a liquidcomposition, a substantial portion of the corticosteroid must bedissolved. As used in reference to the amount of dissolvedcorticosteroid, a “substantial portion” is at least 20% wt., at least30% wt., at least 40% wt., or at least 20% wt and less than 50% wt. ofthe corticosteroid. As used in reference to the amount of dissolvedcorticosteroid, a “major portion” is at least 50% wt. of thecorticosteroid.

Pharmacists working in compounding pharmacies can and do preparesuspension-based formulations comprising corticosteroid. Suchpharmacists will now be able to prepare a single use or multi-use liquidcompositions by employing a method described herein. Alternatively, asubject (patient) undergoing corticosteroid treatment can convert thesuspension-based formulation to a liquid formulation of the invention byemploying a method described herein. Instead of preparing the liquidformulation from the suspension at the pharmacy, a kit containing thesuspension formulation and SAE-CD can be prepared.

The concentration of SAE-CD in solution can be expressed on a weight toweight or weight to volume basis; however, these two units areinterconvertible. When a known weight of cyclodextrin is dissolved in aknown weight of water, the % w/w cyclodextrin concentration isdetermined by dividing the cyclodextrin weight in grams by the totalweight (cyclodextrin+water weight) in like units and multiplying by 100.When a known weight of cyclodextrin is dissolved to a known totalvolume, the % w/v cyclodextrin concentration is determined by dividingthe cyclodextrin weight in grams by the total volume in milliliters andmultiplying by 100. The correlation between the two cyclodextrinconcentration percentages was experimentally determined by preparingvarious % w/w cyclodextrin solutions and measuring the density of eachwith a pycnometer at 25° C. The density (g/mL) of each % w/w CAPTISOLsolution is presented in the table below.

CAPTISOL Density Viscosity % w/w (g/mL) (Cp, 25 C.) 59.4 1.320 527.049.4 1.259 51.9 39.7 1.202 17.0 29.8 1.149 5.91 19.7 1.095 2.78 8.51.041 1.75 0.0 1.002 1 slope = 0.0053 y-intercept = 0.995 correlation =0.9989

The resulting linear relationship readily enables the conversion ofCAPTISOL concentrations expressed in % w/w to that of % w/v by thefollowing equation:

% w/v=((% w/w*slope)+y-intercept)*% w/w

where the slope and intercept values are determined from a linearregression of the density data in the table. For example, by using theabove equation, a 40% w/w CAPTISOL solution would be equivalent to a˜48.3% w/v CAPTISOL solution.

In some embodiments, the composition comprises less than or about 25%wt./wt. of SAE-CD for administration by nebulizer, or less than or about50% wt./wt. of SAE-CD for administration with metered administrationdevices.

The nose comprises the nostrils, or nares, which admit and expel air forrespiration, nose hairs (vibrissae), which catch airborne particulatecontaminants and prevent them from reaching the lungs, olfactory mucosa,and the nasal cavity. Within the nasal cavity, target sites for deliveryor active agent include the middle meatus, superior turbinate andposterior regions. The paranasal sinuses (paranasal sinus cavities) areconnected to the nasal cavity by small orifices call ostia. Theparanasal sinuses include the: (1) the maxillary sinuses, also calledthe antra, which are located under the eyes, in the upper jawbone; (2)the frontal sinuses, which lie above the eyes, in the bone of theforehead; (3) the ethmoid sinuses, positioned between the nose and theeyes, backwards into the skull; and (4) the sphenoid sinuses, which aremore or less in the centre of the skull base.

The nasal cavity and the paranasal sinuses are lined with mucosa. Thesemucosae can be often affected by conditions such as allergies andinfections. Nasal administration of the solutions of the methods,systems, devices, and compositions of the invention provide improvedmeans to deliver therapeutically useful active agents to these mucosaeand to treat diseases, disorders and/or symptoms thereof.

Anatomically, the eyes and nose are connected via the nasolacrimal ductand indirectly through local neurosensory (e.g. the trigeminal nerve)mechanisms. Allergens and allergic treatments from the ocular surfacedrain through the nasolcarimal duct into the inferior turbinate of thenose. Through the nasolacrimal duct, ocular treatments can affect nasalsymptoms in patients suffering from allergic rhinitis. Fluids can travelfrom the eyes to the nose within five minutes, and topical treatmentscan positively affect nasal symptoms induced by a conjunctival allergenchallenge (Spangler et al., Clin Ther 25(8): 2245-2267 (2003)). Thus,topical ocular treatments can be beneficial in treating both ocular andnasal symptoms of allergic rhinitis.

The paranasal sinuses are, under normal circumstances, poorly ventilatedduring breathing. Most of the air exchange of the sinuses occurs throughthe diffusion of air through the ostia, whereas little or no convectiveflow is observed. If an aerosol, such as a therapeutic aerosol generatedby a conventional nebuliser, is inspired through the nose, the aerosolwill flow through the nasal cavity. Since there is virtually no activeflow into the paranasal sinuses, very little or almost none of theaerosol is deposited therein. However, the droplet size of the aerosolor mist administered nasally to a subject can be varied to providepreferential deposition in the nasal cavity versus paranasal sinuscavities or vice versa. The relative percentage of paranasal sinuscavity deposition can be increased by employing a nasal administrationdevice capable of generating appropriately sized droplets and/or capableof generating a variable pressure aerosolized plume.

The mass median diameter (MMD) which will lead to the relatively largestaerosol deposition can depend on individual factors, in particular onthe geometry of the paranasal sinuses including the ostia through whichthe aerosol reaches the sinuses. For example, the volume of the sinusesand the diameter of the ostia differ substantially between individuals.A larger diameter of the ostia is believed to favor the entrance oflarger aerosol droplets into the sinuses, even though the diameters ofthe ostia and of the droplets are of completely different magnitudes. Ifthe individual sinunasal anatomy, or a parameter derived therefrom, of aperson to be treated with an aerosol is at least partially known, it ispossible to select a particular MMD for optimised sinunasal or sinusdelivery.

The target site for delivery of the formulation will depend upon the MMDof droplets (aerosol, mist, vapor, plume, or spray) administered to asubject. Generally, the smaller the droplet size the greater thepercentage of paranasal sinus cavity, turbinate, and/or posterior nasalcavity deposition, and vice versa. In order to maximize nasal delivery(nose, sinus cavity, nasopharyngeal cavity, nasal vestibule, anteriorregion, superior turbinate, middle turbinate, inferior turbinate, and/orolfactory region), the formulation can be administered nasally and theMMAD can be at least about 3.5 microns, at least about 5 microns, atleast about 10 microns, at least about 20 microns, at least about 35microns, at least about 50 microns, at least about 100 microns, or atleast about 150 microns.

In some embodiments, the MMD of the droplets in the aerosol (liquidphase dispersed within a continuous gas phase) can range from about 2 μmto about 6 μm, as measured by laser diffraction. In some embodiments,the most useful MMD for depositing the aerosol in the nasal cavity andin the paranasal sinuses can range from 3 μm to 3.5 μm. In someembodiments, the aerosol of the invention can have a MMD of about 2.5 μmto about 4.5 μm, about 3 μm to about 4 μm, or about 2.8 μm to about 3.5μm. In further embodiments, the MMD is approximately 2.8 μm±0.2 μm, 3.0μm±0.2 μm, 3.2 μm±0.2 μm, 3.4 μm±0.2 μm, 3.6 μm±0.2 μm, 3.8 μm±0.2 μm,or 4.0 μm±0.2 μm. Various appropriate analytical apparatuses todetermine the mass median diameter are known and commercially available,such as the Malvern MasterSizer X or Malvern SprayTec. The geometricdistribution of the aerosolised liquid particles or droplets can bedetermined simultaneously with the mass median diameter.

Delivery of active agent to the deep nasal cavity or paranasal sinuscavities can also be promoted by an aerosol generating administrationdevice comprising a droplet dispersion chamber suitable to provide forvortical particle flow of the aerosol prior to administration to asubject, wherein the administration device is capable of producingdroplets substantially having a uniform mean diameter from about 5 μm toabout 30 μm, about 8 μm to about 25 μm, about 10 μm to about 20 μm,about 10 μm to about 17 μm, about 10 μm to about 15 μm, and about 12 μmto about 17 μm. In some embodiments, the aerosol comprises dropletssubstantially having a uniform mean diameter of about 2 μm to about 50μm, about 5 μm to about 50 μm, about 5 μm to about 40 μm, about 5 μm toabout 35 μm, about 5 μm to about 30 μm, about 5 μm to about 20 μm, about5 μm to about 17 μm, about 5 μm to about 15 μm, about 8 μm to about 30μm, about 8 μm to about 25 μm, about 8 μm to about 20 μm, about 10 μm toabout 30 μm, about 10 μm to about 25 μm, about 11 μm to about 40 μm,about 11 μm to about 30 μm, about 11 μm to about 20 μm, about 11 μm toabout 15 μm, about 15 μm to about 25 μm, about 15 μm to about 20 μm, orabout 17 μm to about 23 μm. The phrase “substantially having a uniformmean diameter,” as used herein with respect to the particle diameterranges, refers to the use of particle collections, wherein at least 50%,at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, orat least 98% have the preferred diameter range. In some embodiments, atleast 60%, at least 70%, at least 80%, at least 90% or at least 95% ofthe nebulized particles are of the particle diameter range. In someembodiments, at least 70%, at least 80%, at least 90% or at least 95% ofthe nebulized particles are of the particle diameter range. The ViaNaseID™ (Kurve, Bothell, Wash.) electronic atomizer is particularly suitablefor this mode of administration, and it delivers an aqueous liquidcomposition at a rate of about 0.1 mL/min.

Another method of promoting paranasal sinus cavity delivery of thecomposition is by: providing the liquid composition; and aerosolizingthe liquid composition with an aerosol generator capable of emitting anaerosol whose pressure pulsates with a frequency in the range from about10 Hz to about 90 Hz, wherein the aerosol generator is adapted tomaintain an amplitude of pressure pulsation of the emitted aerosol of atleast about 5 mbar. In some embodiments, the liquid composition has avolume of less than or about 5 mL. An aerosol flow which is superimposedwith pressure fluctuations, or pressure pulses, creates periodictransient pressure gradients extending from the actively ventilatednasal cavity through the ostia to the paranasal sinuses, which gradientscause a short period of convective flow of air and aerosol into thesinuses until the pressure therein has become equal to the air pressurein the nasal cavity. A portion of the aerosol droplets which thus enterthe paranasal sinuses are deposited therein onto the mucosa. The extentto which the aerosol is deposited depends on the droplet size. Dropletsthat are smaller than the preferred particle size are relatively likelyto be expelled from the sinuses during the subsequent pulsation phase inwhich the aerosol pressure, and thus the pressure in the nasal cavity,is lower than the pressure within the sinuses, and during which aconvective flow of air from the paranasal sinuses to the nasal cavityoccurs. In order that an effective flow of air and aerosol into theparanasal sinuses is induced, it is important to generate the pulsatingaerosol with an appropriate device which is capable of emitting suchaerosol, such as the PARI SINUS (including PARI LC Star, PARI LL andPARI Sprint) or VibrENT™ (PARI) nebulizer families whose compressors areadapted to generate a pulsating aerosol by employing pressure pulses ofappropriate frequency and altitude.

Following administration of a dose of active agent to a subject, therelative percentage of the dose delivered to the nasal cavity versus theparanasal sinus cavities can vary such that: 1) a major portion (greaterthan 50% wt.) of the dose is delivered to the nasal cavity and a minorportion (less than 50% wt.) of the dose is delivered to the paranasalsinus cavities; 2) a major portion (greater than 50% wt.) of the dose isdelivered to the paranasal sinus cavities and a minor portion (less than50% wt.) of the dose is delivered to the nasal cavity; or 3)approximately 50% wt. of the dose is delivered to each the nasal cavityand the paranasal sinus cavities.

The invention can provide at least about 30% wt., at least about 40%wt., at least about 50% wt., at least about 60% wt., at least about 70%wt., at least about 80% wt., at least about 90% wt. or at least about95% wt. for delivery of active agent into the nasal cavity and/orparanasal sinus cavities based upon the emitted dose.

As drug in solution will be distributed equally in the large and smalldroplets leaving the nebulizer, the fine particle fraction will containmore corticosteroid resulting in a greater inspirable dose that canreach the paranasal sinus cavities.

The in-vitro spray characteristics of the budesonide containing aqueouspreparations of Example 33 were determined. The spray pattern at 3 and 6cm, droplet size using a Malvern SprayTec, and respirable fraction usinga cascade impactor were determined for Solution A and Suspension B.There were no apparent differences between Solution A and Suspension Bin terms of axis lengths and ovality ratios at each spray distance. Theaverage droplet size (D50) was 35 μm and 38 μm, respectively. The smalldroplets (D10) were 17 μm and 17 μm, respectively. The respirablefraction (%<9 μm) averaged less than 1% for both Solution A andSuspension B.

The performance of a solution of the invention in a nebulizer can dependupon the viscosity of the solution in its reservoir, the nebulizationsolution. The viscosity of an aqueous solution of SBE7-β-CD changes withrespect to concentration approximately as indicated in the table above.Viscosity of the composition can have an impact on percentage ofnebulization composition emitted from a nebulizer, output rate ofnebulized corticosteroid and droplet size distribution.

The amount of residual composition left in the reservoir of thenebulizer may be greater for solutions containing SAE-CD than for abudesonide-containing suspension. Under similar nebulization conditions,some nebulizers more efficiently reduce the volume of nebulizationsuspension than of nebulization solution in the reservoir of thenebulizer; however, this does not necessarily correspond with the totalamount of drug emitted by the nebulizer.

In other words, the output rate of an SAE-CD nebulization solutionversus that of a suspension can differ such that the solution has ahigher output rate (in terms of drug output) than does the suspension.

An SAE-CD (SBE7-β-CD) concentration of less than or about 25% wt./wt.was identified as the approximate upper acceptable level for acomposition adapted for use in a nebulizer, “acceptable” being definedas the upper concentration of SAE-CD that can be used without buildingup excessive viscosity, which can adversely affect the nebulization timeand output rate. An SAE-CD concentration of less than or about 50%wt./wt. was identified as the approximate upper acceptable level for acomposition adapted for use in a metered administration device. Thepractical upper limit for concentration of SAE-CD will vary among theparticular type of administration device used. The upper acceptableconcentration of SAE-CD in a liquid composition can vary according tothe DS of the derivative, the alkyl chain length of the sulfoalkylfunctional group, and/or the CD ring size of the SAE-CD.

Viscosity of the liquid composition can impact droplet size and dropletsize distribution of the aerosolized composition. For example, thepresent compositions tend to form larger droplets, in terms of Dv50, atthe lower concentrations, and thereby lower viscosity, of SAE-CD in theabsence of corticosteroid, e.g. budesonide. A significant portion of theaerosolized mass is of a respirable size range. Moreover, the solutionscontaining SAE-CD apparently form droplets that are comparable in sizeto those of the nebulized suspension.

A solution (aqueous liquid composition) made by mixing a suspension ofcorticosteroid with SAE-CD is suitable for use in a variety of differentair driven jet nebulizers.

The SAE-CD containing solutions are suitable for administration with anadministration device, e.g. by nebulization, across a range ofconcentrations. Moreover, the droplet size distribution can be partiallycontrolled by adjusting the concentration of SAE-CD.

Depending upon the nebulizer used, the conditions under which thenebulizer is operated and the concentration of SAE-CD in solution,different maximum output rates can be achieved. Use of SAE-CD in acomposition, however, can result in an increased output rate ofcorticosteroid, e.g. budesonide, regardless of the format of theadministration device.

Accordingly, the total nebulization time of the AERONEB GO is one fourththe time to sputter for the Pari LC+ air jet nebulizer. As a result,treatment time would be reduced with the pulsating membrane nebulizer ascompared to the air jet nebulizer, and the amount of budesonide emittedfrom the pulsating membrane nebulizer is 2 to 3 times more than from theair jet nebulizer. It was also determined that the percent of drugexiting the nebulizer (the emitted dose) was 81% of the amount initiallyloaded into the reservoir (the nominal dose). Hence, less drug wouldneed to be loaded into the pulsating membrane nebulizer to treat thepatient in need thereof to provide the same “dose to subject” asprovided by an air jet nebulizer.

A comparison of the AUC data can be made by consideration of the dosedelivered to each subject (“dose to subject”) or dose delivered to thenasal or paranasal cavities of each subject (“dose to nose”) or dosedelivered to the ocular surface of each subject (“dose to eye”) or doseemitted by the administration device (“emitted dose”) or dose availablefor administration or delivery (“nominal dose” or “nominal availabledose” or “loaded dose”).

Practice of the method or system of the invention with the compositionof the invention can result in differences in the amount ofcorticosteroid absorbed systemically when compared to administration ofa suspension-based corticosteroid composition, e.g. RHINOCORT AQUA. Insome embodiments, the composition, method and system of the inventionprovide a higher AUC ((pg*h/mL)/μg of corticosteroid administered),lower AUC, or approximately the same AUC as does a suspension-basedcorticosteroid composition administered under substantially the sameconditions. Similarly, in some embodiments, the composition, method andsystem of the invention provide a higher Cmax (pg of corticosteroid/mLof plasma), lower Cmax, or approximately the same Cmax as does asuspension-based corticosteroid composition administered undersubstantially the same conditions.

The solutions of the invention can provide an enhanced pharmacokineticprofile over suspension-based formulations following their nasal orophthalmic administration.

The corticosteroids that are useful in the present invention generallyinclude any steroid produced by the adrenocortex, includingglucocorticoids and mineralocorticoids, and synthetic analogs andderivatives of naturally occurring corticosteroids havinganti-inflammatory activity. Suitable synthetic analogs include prodrugsand ester derivatives. Examples of corticosteroids that can be used inthe compositions of the invention include aldosterone, beclomethasone,betamethasone, budesonide, ciclesonide (Altana Pharma AG), cloprednol,cortisone, cortivazol, deoxycortone, desonide, desoximetasone,dexamethasone, difluorocortolone, fluclorolone, flumethasone,flunisolide, fluocinolone, fluocinolone acetonide, fluocinonide,fluocortin butyl, fluorocortisone, fluorocortolone, fluorometholone,flurandrenolone, fluticasone, fluticasone valerate, halcinonide,hydrocortisone, icomethasone, loteprednol etabonate, meprednisone,methylprednisolone, mometasone, paramethasone, prednisolone, prednisone,rofleponide, RPR 106541, tixocortol, triamcinolone, and their respectivepharmaceutically acceptable derivatives, such as beclomethasonedipropionate (anhydrous or monohydrate), beclomethasone monopropionate,dexamethasone 21-isonicotinate, fluticasone propionate, icomethasoneenbutate, tixocortol 21-pivalate, and triamcinolone acetonide. In someembodiments, the corticosteroid is beclomethasone dipropionate,budesonide, flunisolide, fluticasone propionate, mometasone furoate,triamcinolone acetonide, or a combination thereof. Other corticosteroidsnot yet commercialized, but that are commercialized subsequent to thefiling of this application, are considered useful in the presentinvention unless it is otherwise established experimentally that theyare not suitable.

Corticosteroids can be provided as the UDB (unit dose budesonide)formulation (Sheffield Pharmaceuticals, Inc.), VANCENASE AQ(beclomethasone dipropionate aqueous suspension; Schering Corporation,Kenilworth, N.J.), ATOMASE (beclomethasone dipropionate aqueoussuspension; Douglas Pharmaceuticals Ltd., Aukland, Australia), BECONASE(beclomethasone dipropionate aqueous suspension; Glaxo Wellcome,NASACORT AQ (triamcinolone acetonide nasal spray, AventisPharmaceuticals), TRI-NASAL (triamcinolone acetonide aqueous suspension;Muro Pharmacaceuticals Inc.) and AEROBID-M, (flunisolide inhalationaerosol, Forest Pharmaceuticals), NASALIDE and NASAREL (flunisolidenasal spray, Ivax Corporation), FLONASE (fluticasone propionate,GlaxoSmithKline), VERAMYST (fluticasone furoate, GSK) and NASONEX(mometasone furoate, Schering-Plough Corporation). Corticosteroidscommercially available for ophthalmic administration includeperdnisolone sodium phosphate ophthalmic solution (INFLAMASE) andprednisolone acetate opthalmic solution (PRED FORTE). SAE-CD can beadded to all such commercial formulations to provide a composition ofthe invention.

Corticosteroids can be grouped according to their relative lipophilicityas described by Barnes et al. (Am. J. Respir. Care Med. (1998), 157, p.S1-S53), Miller-Larsson et al. (Am J. Respir. Crit. Care Med. (2003),167, A773), D. E. Mager et al. (J. Pharm. Sci. (November 2002), 91(11),2441-2451) or S. Edsbäcker (Uptake, retention, and biotransformation ofcorticosteroids in the lung and airways. In: Schleimer R P, O'Byrne PMO,Szefler S J, Brattsand R, editor(s). Inhaled steroids in asthma:optimizing effects in the airways. New York: Marcel Dekker, 2002:213-246). Generally, the less lipophilic a corticosteroid is, the lowerthe amount of SAE-CD required to dissolve it in an aqueous medium andvice versa.

Some embodiments of the invention comprise a corticosteroid having alipophilicity approximating or exceeding that of flunisolide. Someembodiments of the invention comprise a corticosteroid having alipophilicity less than that of flunisolide. Some embodiments of theinvention exclude a corticosteroid having a lipophilicity less thanflunisolide, i.e., embodiments excluding hydrocortisone, prednisolone,prednisone, dexamethasone, betamethasone, methylprednisolone,triamcinolone, and fluocortolone.

Corticosteroids that are less lipophilic than flunisolide generallyrequire a SAE-CD to corticosteroid molar ratio of less than 10:1 todissolve the corticosteroid in an aqueous medium. Exemplarycorticosteroids of this group include hydrocortisone, prednisolone,prednisone, dexamethasone, betamethasone, methylprednisolone,triamcinolone, and fluocortolone. Some embodiments of the inventionexclude corticosteroids that are less lipophilic than flunisolide. Otherembodiments of the invention include corticosteroids that are morelipophilic than flunisolide.

Corticosteroids that are at least as lipophilic as or more lipophilicthan flunisolide generally require a SAE-CD to corticosteroid molarratio of more than 10:1 to dissolve the corticosteroid in an aqueousmedium. In some embodiments, the corticosteroid used in the invention isat least as lipophilic as or more lipophilic than flunisolide. Exemplarycorticosteroids of this group include beclomethasone, beclomethasonedipropionate, beclomethasone monopropionate, budesonide, ciclesonide,desisobutyryl-ciclesonide, flunisolide, fluticasone, fluticasonepropionate, mometasone, mometasone furoate, and triamcinolone acetonide.

Budesonide ((R,S)-11β,16α,17,21-tetrahydroxypregna-1,4-diene-3,20-dionecyclic 16,17-acetal with butyraldehyde; C₂₅H₃₄O₆; Mw: 430.5) is ananti-inflammatory corticosteroid that exhibits potent glucocorticoidactivity.

Commercial formulations of budesonide are sold by AstraZeneca LP(Wilmington, Del.) under the trademarks ENTOCORT EC, PULMICORT RESPULES,RHINOCORT AQUA, RHINOCORT NASAL INHALER and PULMICORT TURBOHALER, andunder its generic name. PULMICORT RESPULES suspension, which is asterile aqueous suspension of micronized budesonide, is administered byinhalation using a nebulizer. The general formulation for a unit dose ofthe PULMICORT RESPULES is set forth in U.S. Pat. No. 6,598,603, and itis an aqueous suspension in which budesonide is suspended in an aqueousmedium comprising about 0.05 to 1.0 mg of budesonide, 0.05 to 0.15 mg ofNaEDTA, 8.0 to 9.0 mg of NaCl, 0.15 to 0.25 mg of polysorbate, 0.25 to0.30 mg of anhydrous citric acid, and 0.45 to 0.55 mg of sodium citrateper one mL of water. RHINOCORT NASAL INHALER is a metered-dosepressurized aerosol unit containing a suspension of micronizedbudesonide in a mixture of propellants. RHINOCORT® AQUA™ (U.S. Pat. No.6,986,904, U.S. Pat. No. 6,565,832, and U.S. Pat. No. 5,976,573; theentire disclosures of which are hereby incorporated by reference) is anunscented metered-dose manual-pump spray formulation (for nasaladministration) containing a suspension of micronized budesonide in anaqueous medium. A unit dose of the formulation consists of: (a) about 32μg budesonide; and (b) a mixture consisting of (1) microcrystallinecellulose and sodium carboxymethyl cellulose, the mixture present atabout 0.5 to 2.5% by weight of the therapeutic composition, (2)dextrose, (3) Polysorbate 80 present at about 0.005 to 0.5% by weight ofthe therapeutic composition, (4) disodium edetate present at about 0.005to 0.1% by weight of the therapeutic composition, (5) and potassiumsorbate present at about 0.05 to 0.2% by weight of the therapeuticcomposition, wherein the budesonide is in the form of finely dividedparticles, at least 90% of which have a mass equivalent sphere diameterof less than 20 μm, suspended in an aqueous medium. Budesonide iscommercially available as a mixture of two isomers (22R and 22S) and canalso be prepared as a single isomer 22R-budesonide.

The invention also provides compositions comprising a water soluble γ-CDderivative, a corticosteroid (either esterified or unesterified) and anaqueous liquid medium. In certain embodiments, the invention alsoprovides compositions comprising a water soluble β-CD derivative, and anaqueous liquid carrier.

The suitability of a corticosteroid for use in the liquidcomposition/formulation can be determined by performing a phasesolubility binding study as detailed in Example 23. Phase solubilitybinding data is used to determine the saturated solubility of acorticosteroid in the presence of varying amounts of SAE-CD in anaqueous liquid carrier. The phase solubility binding curve depicted inFIG. 3 demonstrates the saturated solubility of budesonide in an aqueousliquid carrier comprising γ-CD, HP-β-CD or SBE7-β-CD. A phase solubilitycurve in the graph defines the boundary for the saturated solubility thecorticosteroid in solutions containing various different concentrationsof cyclodextrin. A molar phase solubility curve can be used to determinethe molar ratio of SAE-CD to corticosteroid or of corticosteroid toSAE-CD at various concentrations of corticosteroid. The area below thephase solubility curve, e.g. of FIG. 3, denotes the region where thecorticosteroid is solubilized in an aqueous liquid medium to provide asubstantially clear aqueous solution. In this region, the SAE-CD ispresent in molar excess of the corticosteroid and in an amountsufficient to solubilize the corticosteroid present in the liquidcarrier. The boundary defined by the phase solubility curve will varyaccording to the corticosteroid and SAE-CD within a composition orformulation of the invention. The data detailed in Example 23 provides asummary of the minimum molar ratio of SAE-CD to corticosteroid requiredto achieve the saturated solubility of the corticosteroid in thecomposition or formulation of the invention under the conditionsstudied.

Depending upon the corticosteroid used in the formulation, the molarratio of corticosteroid to SAE-CD (or of SAE-CD to corticosteroid) canvary in order to obtain a solution suitable for administration. Someembodiments of the invention include those wherein the corticosteroid toSAE-CD molar ratio is 0.5 to 0.0001 (1:2 to 1:10,000), 1:1 to 1:100, 1:1to 1:10,000, 0.1 (1:10) to 0.03 (1:33.33), about 0.072 (1:13.89 or about1:14) to 0.0001 (1:10,000), or 0.063 (1:15.873 or about 1:16) to 0.003(1:333.33 or about 1:333). In some embodiments, the corticosteroid isbudesonide and the molar ratio of SAE-CD to budesonide is greater than10:1, or at least 14:1.

In some embodiments, the minimum molar ratio of SAE-CD to corticosteroidis about 1:1 or greater, about 1.5:1 or greater, about 1.6:1 or greater,about 1.8:1 or greater, about 2:1 or greater, about 2.2:1 or greater,about 3:1 or greater, about 3.4:1 or greater, about 3.8:1 or greater,about 4:1 or greater, about 5:1 or greater, about 5.7:1 or greater,about 6:1 or greater, about 7:1 or greater, about 8:1 or greater, about8.8:1 or greater, about 9:1 or greater, greater than about 10:1, about12:1 or greater, greater than about 11:1, greater than about 13:1,greater than about 14:1, about 16:1 or greater, about 20:1 or greater,about 25:1 or greater, about 30:1 or greater, about 40:1 or greater. Insome embodiments, the molar ratio of SAE-CD to corticosteroid rangesabout from >10:1 to about 1000:1, about from >10:1 to about 100:1, aboutfrom >10:1 to about 50:1, about from >10:1 to about 30:1, aboutfrom >10:1 to about 500:1. In some embodiments, the maximum molar ratioof SAE-CD to corticosteroid can be about 4,000:1 or less, about 3,000:1or less, about 2,000:1 or less, about 1,500:1 or less, about 1,400:1 orless, about 1,200:1 or less, about 1,000:1 or less, about 900:1 or less,about 800:1 or less, about 600:1 or less, about 500:1 or less, about400:1 or less, about 360:1 or less, about 300:1 or less, about 275:1 orless, about 250:1 or less, about 200:1 or less, about 150:1 or less,about 100:1 or less, about 80:1 or less, or about 60:1 or less.Combinations of the upper and lower molar ratios are useful.

The solubility of a corticosteroid in a composition is affected by itsintrinsic solubility in the aqueous medium and its binding constant withSAE-CD. The higher the intrinsic solubility of the corticosteroid, thelesser the amount of SAE-CD required to solubilize a dose of it in thecomposition. The maximum concentration of corticosteroid in an aqueoussolution containing SAE-CD is known as its concentration at saturatedsolubility. The saturated solubility of a corticosteroid in the presenceof a fixed amount of SAE-CD will vary according to the identity of thecorticosteroid and the SAE-CD. The higher the concentration at saturatedsolubility, the more soluble the corticosteroid is in the presence ofSAE-CD. Example 45 summarizes saturated solubility data for somecorticosteroids in the absence (intrinsic solubility of corticosteroidin the aqueous test medium) and in the presence of two differentSAE-CD's as determined herein.

The binding of a corticosteroid to the SAE-CD can be characterized byits equilibrium binding constant. The higher the binding constant, themore tightly the corticosteroid is bound to the SAE-CD. Example 46summarizes the equilibrium binding constants (K) for somecorticosteroids in the presence of CAPTISOL or SBE6.1-γ-CD (0.04 M).

The equilibrium binding constant data can be used in combination withthe phase solubility data (saturated solubility data) to preparecompositions according to the invention having a target concentration ofcorticosteroid and SAE-CD. Accordingly, some embodiments of theinvention comprise a corticosteroid having an intrinsic solubility inwater that approximates or is less than the intrinsic solubility offlunisolide (less than about 11×10⁻⁵ M or less than about 11.3×10⁻⁵ M)in water as determined herein. In some embodiments, the inventioncomprises a corticosteroid having an intrinsic solubility in water thatis greater than that of flunisolide.

Even though a composition or formulation of the invention can comprisethe corticosteroid present in an aqueous medium at a concentration up toits saturated solubility in the presence of a particular concentrationof SAE-CD, some embodiments of the invention include those wherein thecorticosteroid is present at a concentration that is less than itssaturated solubility in the presence of that concentration of SAE-CD.The corticosteroid can be present at a concentration that is 95% orless, 90% or less, 85% or less, 80% or less, or 50% or less of itssaturated solubility as determined in the presence of SAE-CD. It isgenerally easier to prepare solutions that comprise the corticosteroidat a concentration that is less than its saturated solubility in thepresence of SAE-CD.

Therefore, the molar ratio of SAE-CD to corticosteroid in a formulationor composition of the invention can exceed the molar ratio obtained atthe saturated solubility of the corticosteroid in the presence ofSAE-CD, such as defined by the phase solubility binding curve for thecorticosteroid. In such a case, the molar ratio of SAE-CD tocorticosteroid in the composition or formulation can be at least about1%, at least about 2%, at least about 5%, at least about 7.5%, at leastabout 10%, at least about 15%, at least about 20%, at least about 25%,at least about 50%, at least about 75%, at least about 100%, or at leastabout 200% greater than the molar ratio at the saturated solubility ofthe corticosteroid in the presence of SAE-CD. For example, if the molarratio at the saturated solubility is about 14:1, then the molar ratio inthe composition or formulation can be at least about 14.1:1 (for atleast 1% higher), at least about 14.3:1 (for at least 2% higher), atleast about 14.7:1 (for at least 5% higher), at least about 15.4:1 (forat least 10% higher), at least about 16.1:1 (for at least 15% higher),at least about 16.8:1 (for at least 20% higher), at least about 17.5:1(for at least 25% higher), at least about 21:1 (for at least 50%higher), at least about 24.5:1 (for at least 75% higher), at least about28:1 (for at least 100% higher), or at least about 42:1 (for at least100% higher).

Changes in the molar ratio of SAE-CD to corticosteroid can also have animpact upon the dissolution rate of corticosteroid in an aqueous medium.Generally, increasing the molar ratio results in an increase in the rateof dissolution of the corticosteroid.

The corticosteroid compound can be present in the final, dilutedcorticosteroid nebulizable composition in an amount from about 1 μg/mLto about 10 mg/mL, about 10 μg/mL to about 1 mg/mL, or about 20 μg/mL toabout 500 μg/mL. For example, the drug concentration can be betweenabout 30 and 1000 μg/mL for triamcinolone acetonide, and between about50 and 2000 μg/mL for budesonide, depending on the volume to beadministered. By following the preferred methods of the presentinvention, relatively high concentrations of the corticosteroid can beachieved in an aqueous-based composition.

Similarly, the corticosteroid compound is present in the final, dilutedcorticosteroid composition designed for nasal administration in anamount from about 10 μg/mL to 6 mg/mL, 50 μg/mL to about 10 mg/mL, about100 μg/mL to about 2 mg/mL, or about 300 μg/mL to about 1 mg/mL. Forexample, the drug concentration can range from about 250 μg/mL and about1 mg/mL or about 250 μg/mL and about 6 mg/mL for triamcinoloneacetonide, and range from about 400 μg/mL to about 1.6 mg/mL, 40 μg/mLto about 6 mg/mL, 40 μg/mL to about 3 mg/Ml, 250 μg/mL to about 6 mg/mL,or about 250 μg/mL to about 3 mg/mL for budesonide, depending on thevolume to be administered.

For the treatment of nasal cavity, paranasal sinus cavity, and/orophthalmic disease, symptoms or disorders, the corticosteroidcomposition is prepared as described herein. The corticosteroid for suchtreatment can be, beclomethasone dipropionate, beclomethasonemonopropionate, betamethasone, budesonide, ciclesonide,desisobutyryl-ciclesonide, flunisolide, fluticasone, fluticasonepropionate, fluticasone furoate, mometasone, mometasone furoate, ortriamcinolone acetonide, and can be formulated in the concentrations setforth herein.

The corticosteroid or any other therapeutic (active) agent herein can bepresent in its neutral, ionic, salt, basic, acidic, natural, synthetic,diastereomeric, isomeric, enantiomerically pure, enantiomericallyenriched, racemic, solvate, anhydrous, hydrate, hemi-hydrate,sesqui-hydrate, chelate, derivative, analog, esterified, non-esterfied,polymorph, co-crystal, other common form, or a combination thereof. Whenused in reference to a therapeutic agent, “combination thereof” is takento mean a combination of any two or more of the forms of the therapeuticagent defined herein. Accordingly, whenever a therapeutic agent is namedherein, all such forms available are included. For example, all knownforms of budesonide are considered within the scope of the invention.

As used herein, a dose includes a unit dose, a nominal dose, emitteddose, nominal available dose, dose to subject, dose to nose, dose toeye, or other such term of art. Unless otherwise specified, the term a“unit dose” is a single dose, such as a single spray from a meteredspray device. An administration of an effective amount, effective dose,or therapeutically effective amount to a subject can comprise one ormore unit doses. In certain embodiments, the effective dose can be asingle unit dose administered to one nostril or one eye. In certainembodiments, the therapeutically effective amount can be two unit dosesadministered to one nostril or one eye. In certain embodiments, theeffective dose can be two unit doses, with one unit dose administered toeach eye or each nostril. In some embodiments, the therapeuticallyeffective amount can be more than two unit doses, with more than onedose administered to a nostril(s) or eye(s). The term “effective amount”or “effective dose” or “therapeutically effective amount” is the amountor quantity of active agent that is sufficient to elicit the required ordesired therapeutic effect, or the amount that is sufficient to elicitan appreciable biological response when administered to a subject whengiven at one event or period of administration. A single period ofadministration can comprise administration of 1, 2, 3, 4, 5, 6, 7, 8, ormore unit doses. For administration with a nebulizer, or any otherdevice that continuously generates an aerosol over a period of time, the“period of administration” is that period of time required to deliver atherapeutically effective amount of an active agent to one or bothnostrils of a subject. For administration with a nebulizer, or any otherdevice that continuously generates an aerosol over a period of time, theunit dose is an amount contained in the reservoir of the device that isdelivered in one period of administration, i.e., for a nebulizer, theunit dose is the therapeutically effective dose delivered in one periodof administration. A nebulizer can contain a single unit dose that isadministered over a single period of administration. Alternatively, anebulizer can contain multiple unit doses that are administered inmultiple periods of administration, for example, 1 to 8 unit dosesadministered in 1 to 8 periods of administration. A nebulizer can alsocontain multiple reservoirs containing single or multiple unit doses.For administration with a metered administration device, i.e., a devicethat provides a fixed volume or amount of composition upon actuation,e.g., pump nasal spray, squeeze bottle, atomizer, dropper, and othersimilar devices, the event of administration, for delivery of aneffective dose, is a predetermined number of actuations of the devicewhich releases a corresponding predetermined number of unit doses, e.g.,1 to 8 actuations of the administration device releases 1 to 8 unitdoses in one or both nostrils of a subject. The unit dose of activeagent delivered is assumed to be the amount of active agent emitted fromthe administration device, i.e., the emitted dose.

The term “nominal dose” refers to an amount of active agent placed inthe reservoir of a nebulizer, wherein the volume of liquid in thereservoir is determined according the size of the reservoir. The term“nominal available dose” refers to the amount of active agent that isdetermined could be or should have been available to a subject whenadministered a formulation of the invention by nebulization butformulation is/was not administered in its entirety. The term “emitteddose” refers to the amount of active agent emitted from a nebulizer. Theterm “dose to subject” refers to the amount of active agent delivered toand retained by a subject following administration of a formulation ofthe invention by nebulization. The term “dose to nose” refers to theamount of active agent delivered to and retained by the nose (nasalcavity and/or paranasal sinus cavities) of a subject followingadministration of a formulation of the invention by nebulization.

The daily dose of the corticosteroid is generally about 0.05 mg to 10mg, depending on the drug and the disease, in accordance with the 2006Physician's Desk Reference (PDR). However, in view of the improvedbioavailability of a corticosteroid when administered as a solution ofthe invention, the dose required to achieve a desired clinical endpoint,clinical benefit or therapeutic benefit can be lower than thecorresponding dose indicated in the PDR.

The following table provides exemplary dosing regimens for variouscorticosteroids as included in the commercially available branded nasaladministration products in particular dosage strengths. The compositionof the invention can be dosed according to these same dosing regimens orother dosing regimens herein.

Drug Amount per Total unit dose Weight/ Generic Name/ (Total Dose Rangeper Volume Brand Name Dosing Regimen day) administered Beclomethasone1-2 sprays in each nostril 42 mcg 100 mg Dipropionate twice daily(168-336 mcg/day) Beconase ® AQ (GSK) Ciclesonide 2 sprays in eachnostril once 50 mcg 70 μL Omnaris ® daily (200 mcg/day) (Sepracor)Fluticasone Starting: 2 sprays in each 50 mcg 100 mg Propionate nostrilonce daily or 1 spray Starting: (200 mcg/day) Flonase ® twice dailyMaintenance: (100 mcg/ (GSK) Maintenance: day) 1 spray in each nostrilonce daily Fluticasone Starting: 2 sprays in each 27.5 mcg 50 μL Furoatenostril once daily Starting: (110 mcg/day) Veramyst ® Maintenance:Maintenance: (55 mcg/ (GSK) 1 spray in each nostril once day) dailyBudesonide 1-2 sprays in each nostril 32 mcg (64 mcg in 51 mgRhinocort ® once or twice daily Canada) Aqua (64-320 mcg/day) (AZ)Triamcinolone 2 sprays in each nostril once 55 mcg 100 mg Acetonidedaily (220 mcg/day) Nasacort ® AQ (Sanofi- Aventis) Mometasone 2 spraysin each nostril once 50 mcg 100 mg Furoate daily (200 mcg/day) Nasonex ®(Schering- Plough) Flunisolide 2 sprays in each nostril 29 mcg-Nasarel(232-464 mcg/ 100 mg Nasarel ® twice daily day) (Ivax) Titrate: 2 spraysper nostril three times daily Dexamethasone 84 mcg (inhalationDexacort ® Turbinaire vapor) (USB) Betamethasone + 2-3 drops instilledin each Strength: 1 mg/mL 0.13-0.20 mL Neomycin nostril 2-3 times daily(1.04 mg-3.6 mg/day) sulphate Betnesol-N ® Nasal Drops (GSK) Fluticasone1 nasule contents instilled in 400 mcg/Nasule 400 μL Propionate eachnostril 1-2 times daily (400-800 mcg/day) Flixonase ® Nasule Drops(Allen & Hanbury/GSK) Dexamethasone + 1 spray per nostril up to 6Dexamethasone: 20 mcg; tramazoline times daily; not for use for (40-240mcg/ HCl more than 14 consecutive day)_Tramazoline: (Dexa- days 120 mcgRhinapray ® (240-1440 mcg/day) Duo

Dosing Total Drug Drug Regimen per Delivered Per Generic Name Brand NameStrength Affected Eye Day* Dexamethasone Maxidex ® 0.1% w/v 1-2 dropsevery 0.16-0.48 mg* (susp) (Alcon) 4-6 hours Dexamethasone Decadron ®0.1% w/v 1-2 drops every 0.8-1.6 mg* Sodium (Merck) hour while Alsoassumes 20 phosphate (soln) awake & every drops/day 12 hours at nightFluorometholone Fluor-Op ® 0.1%, 0.25% w/v 1 drop 2-4 0.06-0.24 mg(Novartis) times a day Loteprednol Alrex ® 0.2% w/v 1 drop 4 times a0.32 mg* etabonate (Bausch & day Lomb) Prednisolone Pred-Forte ® 0.12%,0.125, 1% w/v 1-2 drops 2 to 4 1.2-9.4 mg (for Acetate (susp) (Allergan)times a day the 1% susp) Prednisolone Inflamase 0.125%, 0.1% w/v 1-2drops every 0.8-2 mg* Sodium Forte ® hour while Also assumes 20Phosphate (soln) (Novartis) awake & every drops/day 12 hours at night

The following table provides exemplary dosing regimens for variouscorticosteroids as included in the commercially available branded ocularadministration products in particular dosage strengths. The compositionof the invention can be dosed according to these same dosing regimens orother dosing regimens herein.

*A typical volume of an eye drop has been found to range from 25 to 50mcL. So if the volume is not specified in the product label, it wasassumed for the purposes of this chart that the volume is 40 mcL asindicated by a asterisk.

A dose of corticosteroid, such as budesonide, can also be administeredonce daily, once every two days, seven days per week, once every week,once every month, for an extended period of time, such as several days,weeks, or even longer, or even less frequently. A dose of budesonide, orcorticosteroid, can be administered twice, thrice or more times per dayor on an as-needed basis. Administration can be during the daytimeand/or nighttime. In some embodiments, such as set forth in U.S. Pat.No. 6,598,603 and U.S. Pat. No. 6,899,099, a dose comprises 0.05 to 2.0mg or 0.25 to 1.0 mg of budesonide.

In some embodiments, a dose comprises about 1 μg to about 20 mg, about 1μg to about 10 mg, about 0.01 mg to about 10 mg, about 0.025 mg to about10 mg, about 0.05 mg to about 5 mg, about 0.1 mg to about 5 mg, about0.125 mg to about 5 mg, about 0.25 mg to about 5 mg, about 0.5 mg toabout 5 mg, about 0.05 mg to about 2 mg, about 0.1 mg to about 2 mg,about 0.125 mg to about 2 mg, about 0.25 mg to about 2 mg, about 0.5 mgto about 2 mg, about 10 μg to about 2.5 mg, about 5 μg to about 500 μg,about 5 μg to about 250 μg, about 5 μg to about 130 μg, about 45 μg toabout 1000 μg, about 1 μg, about 10 μg, about 16 μg, about 25 μg, about27.5 μg, about 29 μg, about 32 μg, at least about 25 μg, about 40 μg,about 42 μg, about 45 μg, about 48 μg, about 50 μg, about 55 μg, about64 μg, about 84 μg, about 96 μg, about 100 μg, about 125 μg, about 128μg, about 200 μg, about 250 μg, about 400 μg, about 800 μg, about 25 μgto about 66 μg, about 48 μg to about 81 μg, about 73 μg to about 125 μg,about 95 μg, about 35 μg to about 95 μg, about 25 μg to about 125 μg,about 60 μg to about 170 μg, about 110 μg, about 170 μg, about 45 μg toabout 220 μg, about 45 μg to about 85 μg, about 48 μg to about 82 μg,about 85 μg to about 160 μg, about 140 μg to about 220 μg, about 120 μgto about 325 μg, about 205 μg, about 320 μg, about 325 μg, about 90 μgto about 400 μg, about 95 μg to about 170 μg, about 165 μg to about 275μg, or about 275 μg to about 400 μg of corticosteroid, such asbudesonide, said dose being a unit dose, nominal dose, nominal availabledose, emitted dose, delivered dose, dose to subject, dose to eye, ordose to nose.

Some embodiments of the invention also provide a unit dose of atherapeutic corticosteroid solution comprising: about 32 μg to 64 μg ofbudesonide; SAE-CD; pharmaceutically acceptable aqueous liquid carrier;disodium edetate present at of about 0.005 to about 0.1% by weight ofthe therapeutic composition unit dose; and potassium sorbate present atof about 0.05 to about 0.2% by weight of the therapeutic compositionunit dose, and wherein the corticosteroid solution is suitable for nasaladministration to a mammal as a unit dose. subject in need thereof.

Some embodiments of the invention also provide a method of treating,preventing or ameliorating in a subject a corticosteroid-responsivedisease or disorder, the method comprising:

metering into the nose of a mammal a the subject a therapeuticallyeffective amount of budesonide that is less than about 320 μg per day,delivered as 8 or more unit doses, wherein each unit dose consists of:about 32 μg of budesonide; SAE-CD; disodium edetate present at of about0.005 to about 0.1% by weight of the therapeutic composition unit dose;potassium sorbate present at of about 0.05 to about 0.2% by weight ofthe therapeutic composition unit dose; and a pharmaceutically acceptableaqueous liquid carrier. In some embodiments, the therapeuticallyeffective amount of budesonide is delivered as 7 unit doses, 6 unitdoses, 5 unit doses, 4 unit doses, 3 unit doses, 2 unit doses or as oneunit dose. In some embodiments, the unit dose comprises 64 μg, 96 μg,128 μg, 160 μg, 192 μg, 224 μg, 256 μg, 288 μg, or 320 μg of budesonide.

In some embodiments, the corticosteroid solution has a pH of about 3.5to about 5 or about 4.2 to about 4.6.

The corticosteroid can be present at a concentration of about 20 μg toabout 30 mg of corticosteroid per mL of solution. As a result, about 10mg to 500 mg of SAE-CD, or 10 mg to 250 mg of SAE-CD, or 10 mg to 300 mgof SAE-CD per mL or per g of solution in order to dissolve a substantialportion of the corticosteroid.

Due to the wide range of reservoir volumes available for administrationdevices and of varying dose requirements among the corticosteroids, aformulation of the invention can comprise 1 μg to 20 mg ofcorticosteroid in 0.01 mL to 100 mL of solution volume. The compositionsof the invention can comprises a dose or unit dose of corticosteroid inan approximate solution volume of 10 μl to 100 mL, 10 μl to 5000 μl, 10μl to 2.5 mL, 20 μl to 5 mL, 10 μl to 500 t, 10 μl to 200 t, 101 to 400μl, 50 μl to 50 mL, 50 μl to 10 mL, 50 μl to 5 mL, 0.1 to 10 mL, 0.1 mLto less than 10 mL, 0.1 mL to 7.5 mL, 0.1 mL to 5 mL, 0.1 mL to 3 mL,0.1 mL to 2 mL, 0.1 mL to 1 mL, 0.05 mL to 7.5 mL, 0.05 mL to 5 mL, 0.05mL to 3 mL, 0.05 mL to 2 mL, 0.05 mL to 1 mL, 501 to 137 μl, 50 μl to 70μl, 137 μl to 400 μl, 50 μl to 200 μl, 25 μl, 50 μl, 75 μl, 100 μl, 150μl, 200 μl, 250 μl, 500 μl, 750 μl, 1 mL, 2 mL, 5 mL, or 10 mL.

An administration device can be adapted to emit about 10 to about 500μl, about 0.2 to about 5 mL, or about 0.5 to about 100 mL of a liquidcomposition per actuation or per dose. In some embodiments, theadministration device comprises a nozzle which comprises a valve.Together, the nozzle and valve can be adapted to release 25 μl to 260μl, 50 μl to 137 μl, 50 μl to 70 μl, 137 μl to 400 μl, or 51 to 100 mgof a liquid composition of the invention.

The composition of the invention can be packaged for single-use ormulti-use. A single use package comprises a single dose ofcorticosteroid and a multi-use package comprises two or more doses ofcorticosteroid. The packaging can comprise one or more containers. Acontainer can comprise one or more doses. A single use containercomprises a single dose, and a multi-use container comprises two or moredoses. Suitable packaging and containers include, by way of example andwithout limitation, a bottle, vial, ampoule, syringe, blister, capsule,or blow/fill/seal container, or other devices such as those detailed inthe examples. The packaging can in a preservative free system such asthe Advanced Preservative Free system from Pfeiffer, or the Freepod fromValois, or in a single use spray device such as the Pfeiffer BidoseSystem or Unitdose System.

The composition can exit the device as a liquid, gel, vapor, fineaerosol, mist, cloud or plume. Depending upon the mode ofadministration, the composition can be delivered to the nasal cavity,paranasal sinus cavities, or delivered topically to the eye(s) of asubject.

The administration device can employ single use (single dose) ormulti-use (multi-dose) packaging. An administration device can be usedrepeatedly with single use or multi-use packages and/or containers.

The fill volume for the reservoir of a multi-dose, metered dose nasalspray must be sufficient to provide for the number of actuationsrequired to initially prime the spray pump, periodically reprime thepump, and to provide the desired number of doses in a consistent manor.Since the tail-off characteristics (performance when container is nearlyempty) can vary as a function of pump design, container geometry andformulation, the fill volume should be sufficient to compensate for allthese variables. As such, the reservoir in an administration device cancomprise an overfill. As used herein, “overfill” is the amount orpercentage of extra composition (either in terms of the volume or weightof the composition or the amount of drug in the composition) added tothe composition in the reservoir to compensate for the tail-offcharacteristics of the device. In some embodiments, the overfill is atleast about 1%, at least about 2.5%, at least about 5%, at least about7.5%, at least about 10%, at least about 15%, at least about 25%, atleast about 35%, at least about 45%, at least about 50% of the targetvolume or weight of composition in a unit dose or dose of thecomposition.

The time required to administer or deliver a dose of the invention willdepend upon its mode of administration, i.e., the administration deviceused. For administration with an administration device thatsubstantially continuously emits an aerosol over a period of time, e.g.nebulizer, the time required to administer or deliver a dose ofcorticosteroid is less than 30 min, less than 20 min, less than 10 min,less than 7 min, less than 5 min, less than 3 min, or less than 2 min,or the time is about 0.05 min to 10 min, about 0.1 min to 5 min, about0.1 min to 3 min, about 0.1 min to 2 min, about 0.1 min to 1.5 min,about 0.5 min to about 1.5 min, or about 1 min. The time will varyaccording to the dose of active agent in, the concentration of activeagent in, and the volume of the composition in the reservoir of anadministration device, and it will also depend upon the format of theadministration device, aerosolization efficiency, and reservoir volume.In a given administration device, the lower the volume of the liquidcomposition, the more quickly a corresponding dose of active agent isadministered or delivered. The higher the concentration of active agentin the composition, the faster a dose of the active agent can beadministered or delivered.

For metered volume (or metered weight) administration devices thatgenerate a plume or aerosol by actuation, e.g., squeeze bottle pumpspray, pump spray, atomizer, the time for administration of a dose ismerely the time it takes to affect one, two or more actuations of thedevice in one or both nostrils of a subject or about the time it takesfor a subject to take a single breath (about 1 sec to 3 sec, or 1 sec to5 sec).

The formulation of the invention can be used to deliver two or moredifferent active agents (active ingredients, therapeutic agents, etc.).Particular combinations of active agents can be provided by the presentformulation. Some combinations of active agents include: 1) a first drugfrom a first therapeutic class and a different second drug from the sametherapeutic class; 2) a first drug from a first therapeutic class and adifferent second drug from a different therapeutic class; 3) a firstdrug having a first type of biological activity and a different seconddrug having about the same biological activity; 4) a first drug having afirst type of biological activity and a different second drug having adifferent second type of biological activity. Exemplary combinations ofactive agents are described herein.

A corticosteroid, such as budesonide, can be administered as itsisomeric pair or single isomer and in combination with one or more otherdrugs (active ingredients, therapeutic agents, active agents, etc., theterms being used interchangeably herein unless otherwise specified).Such other drugs include: B₂ adrenoreceptor agonist, topical anesthetic,D₂ receptor agonist, anticholinergic agent, anti-infective agent,antibiotic, antifungal agent; hormones such as insulin, growth hormone,growth hormone releasing factor, glucagon, somatostatin, chorionicgonadotropin, adrenocorticotropic hormone (ACTH), and interferon;anti-inflammatory agents such as aspirin, aminopyrine, acetaminophen,ibufenac, ibuprofen, indomethacin, colchicine, sulpyrine, mefenamicacid, phenacetin, phenylbutazone, flufenamic acid and probenecid;antibiotics such as penicillin or its derivatives, cephalosporin or itsderivatives; erythromycin, tetracycline, furadiomycin, leucomycin;chemotherapeutic agents such as sulfathiazole and nitrofurazone; cardiacagents such as digitalis and digoxin; blood vein dilating agents such asnitroglycerin and papaverine hydrochloride; cough curing agents such ascodeine; azulen; phenovalin; pepsin; enzymes such as lysozymehydrochloride; other systemic agents such as antihypertensives anddiuretic; tranquilizers; sex hormone; vitamin; ulcer medication;analgesic; decongestant; expectorant; antitussive; antihistamine agent;bronchodilator; topical anesthetic; sensory agents; oral care agents;miscellaneous respiratory agent; gastrointestinal agent; andcombinations thereof.

B₂-Adrenoreceptor agonists for use in combination with the compositionsprovided herein include, but are not limited to, Albuterol(alpha¹-(((1,1-dimethylethyl)amino)methyl)-4-hydroxy-1,3-benzenedimethanol);Bambuterol (dimethylcarbamic acid5-(2-((1,1-dimethylethyl)amino)-1-hydroxyethyl)-1,3-phenylene ester);Bitolterol (4-methylbenzoic acid4-(2-((1,1-dimethylethyl)amino)-1-hydroxyethyl)-1,2-phenyleneester);Broxaterol(3-bromo-alpha-(((1,1-dimethylethyl)amino)methyl)-5-isoxazolemethanol);Isoproterenol(4-(1-hydroxy-2-((1-methylethyl-)amino)ethyl)-1,2-benzene-diol);Trimetoquinol (1,2,3,4-tetrahydro-1-((3,4-,5-trimethoxyphenyl)-methyl)-6,7-isoquinolinediol); Clenbuterol(4-amino-3,5-dichloro-alpha-(((1,1-diemthylethyl)amino)methyl)benzenemethanol);Fenoterol(5-(1-hydroxy-2-((2-(4-hydroxyphenyl)-1-methylethyl)amino)ethyl)-1,3-benzenediol);Formoterol(2-hydroxy-5-((1RS)-1-hydroxy-2-(((1RS)-2-(p-methoxyphenyl)-1-methylethyl)amino)ethyl)formanilide); (R,R)-Formoterol; Desformoterol ((R,R) or(S,S)-3-amino-4-hydroxy-alpha-(((2-(4-methoxyphenyl)-1-methyl-ethyl)amino)methyl)benzenemethanol);Hexoprenaline(4,4′-(1,6-hexane-diyl)-bis(imino(1-hydroxy-2,1-ethanediyl)))bis-1,2-benzenediol);Isoetharine(4-(1-hydroxy-2-((1-methylethyl)amino)butyl)-1,2-benzenediol);Isoprenaline(4-(1-hydroxy-2-((1-methylethyl)amino)ethyl)-1,2-benzenediol);Meta-proterenol(5-(1-hydroxy-2-((1-methylethyl)amino)ethyl)-1,3-benzened-iol);Picumeterol(4-amino-3,5-dichloro-alpha-(((6-(2-(2-pyridinyl)ethoxy)hexyl)-amino)methyl)benzenemethanol);Pirbuterol(.alpha.⁶-(((1,1-dimethylethyl)-amino)methyl)-3-hydroxy-2,6-pyridinemethanol);Procaterol(((R*,S*)-(.+−.)-8-hydroxy-5-(1-hydroxy-2-((1-methylethyl)amino)butyl)-2(1H)-quinolin-one);Reproterol((7-(3-((2-(3,5-dihydroxyphenyl)-2-hydroxyethyl)amino)-propyl)-3,7-dihydro-1,3-dimethyl-1H-purine-2,6-dione);Rimiterol (4-(hydroxy-2-piperidinylmethyl)-1,2-benzenediol); Salbutamol((.+−.)-alpha¹-(((1,1-dimethylethyl)amino)methyl)-4-hydroxy-1,3-b-enzenedimethanol);(R)-Salbutamol; Salmeterol((.+−.)-4-hydroxy-.alpha¹-(((6-(4-phenylbutoxy)hexyl)-amino)methyl)-1,3-benzenedimethanol);(R)-Salmeterol; Terbutaline(5-(2-((1,1-dimethylethyl)amino)-1-hydroxyethyl)-1,3-benzenediol);Tulobuterol(2-chloro-.alpha.-(((1,1-dimethylethyl)amino)methyl)benzenemethanol);and TA-2005(8-hydroxy-5-((1R)-1-hydroxy-2-(N-((1R)-2-(4-methoxyphenyl)-1-methylethyl)amino)ethyl)carbostyrilhydrochloride).

Dopamine (D₂) receptor agonists include, but are not limited to,Apomorphine((r)-5,6,6a,7-tetrahydro-6-methyl-4H-dibenzo[de,glquinoline-10,11-diol);Bromocriptine ((5′.alpha.)-2-bromo-12′-hydroxy-2′-(1-methylethyl)-5′-(2-methylpropyl)ergotaman-3′,6′,18-trione); Cabergoline((8.beta.)-N-(3-(dimethylamino)propyl)-N-((ethylamino)carbony-l)-6-(2-propenyl)ergoline-8-carboxamide);Lisuride(N′-((8-alpha-)-9,10-didehydro-6-methylergolin-8-yl)-N,N-diethylurea);Pergolide ((8-beta-)-8-((methylthio)methyl)-6-propylergoline); Levodopa(3-hydroxy-L-tryrosine); Pramipexole((s)-4,5,6,7-tetrahydro-N⁶-prop-yl-2,6-benzothiazolediamine); Quinpirolehydrochloride(trans-(−)-4aR-4,4a,5,6,7,8,8a,9-octahydro-5-propyl-1H-pyrazolo[3,4-g]quinolinehydrochloride); Ropinirole(4-(2-(dipropylamino)ethyl)-1,3-dihydro-2H-indol-2-one); and Talipexole(5,6,7,8-tetrahydro-6-(2-propenyl)-4H-thia-zolo[4,5-d]azepin-2-amine).Other dopamine D₂ receptor agonists for use herein are disclosed inInternational Patent Application Publication No. WO 99/36095, therelevant disclosure of which is hereby incorporated by reference.

Anticholinergic agents for use herein include, but are not limited to,ipratropium bromide, oxitropium bromide, atropine methyl nitrate,atropine sulfate, ipratropium, belladonna extract, scopolamine,scopolamine methobromide, homatropine methobromide, hyoscyamine,isopriopramide, orphenadrine, benzalkonium chloride, tiotropium bromideand glycopyrronium bromide. In certain embodiments, the compositionscontain an anticholinergic agent, such as ipratropium bromide ortiotropium bromide, at a concentration of about 5 μg/mL to about 5mg/mL, or about 50 μg/mL to about 200 μg/mL. In other embodiments, thecompositions for use in the methods herein contain an anticholinergicagent, including ipratropium bromide and tiotropium bromide, at aconcentration of about 83 μg/mL or about 167 μg/mL.

Other active ingredients for use herein in combination therapy, include,but are not limited to, IL-5 inhibitors such as those disclosed in U.S.Pat. No. 5,668,110, U.S. Pat. No. 5,683,983, U.S. Pat. No. 5,677,280,U.S. Pat. No. 6,071,910 and U.S. Pat. No. 5,654,276, the relevantdisclosures of which are hereby incorporated by reference; antisensemodulators of IL-5 such as those disclosed in U.S. Pat. No. 6,136,603,the relevant disclosure of which is hereby incorporated by reference;milrinone (1,6-dihydro-2-methyl-6-oxo-[3,4′-bipyridine]-5-carbonitrile);milrinone lactate; tryptase inhibitors such as those disclosed in U.S.Pat. No. 5,525,623, the relevant disclosure of which is herebyincorporated by reference; tachykinin receptor antagonists such as thosedisclosed in U.S. Pat. No. 5,691,336, U.S. Pat. No. 5,877,191, U.S. Pat.No. 5,929,094, U.S. Pat. No. 5,750,549 and U.S. Pat. No. 5,780,467, therelevant disclosures of which are hereby incorporated by reference;leukotriene receptor antagonists such as montelukast sodium (Singular™,R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl-]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]-propyl]thio]methyl]cyclopro-paneaceticacid, monosodium salt), 5-lypoxygenase inhibitors such as zileuton(Zyflo™, Abbott Laboratories, Abbott Park, Ill.), and anti-IgEantibodies such as Xolaimm (recombinant humanized anti-IgE monoclonalantibody (CGP 51901; IGE 025A; rhuMAb-E25), Genentech, Inc., South SanFrancisco, Calif.), and topical anesthetics such as lidocaine,N-arylamide, aminoalkylbenzoate, prilocalne, etidocaine (U.S. Pat. No.5,510,339, U.S. Pat. No. 5,631,267, and U.S. Pat. No. 5,837,713, therelevant disclosures of which are hereby incorporated by reference).

Analgesics useful for this invention include any narcotic andnon-narcotic analgesics, such as menthol, acetaminophen, NSAIDs,salicylates including aspirin (acetylsalicylic acid), salsalate, sodiumsalicylate, diflunisal, etc. and mixtures thereof, indomethacin andoptically active isomers or racemates or active metabolites of NSAIDs(NSAIDs include propionic acid derivatives, acetic acid derivatives,fenamic acid derivatives, biphenylcarboxylic acid derivatives andoxicams) including fenoprofen, flurbiprofen, ibuprofen, ketoprofen,naproxen, oxaprozin, etodolac, indomethacin, ketorolac, nabumetone,sulindac, tolmetin, meclofenamate, mefenamic acid, piroxicam, bromfenac,carprofen, tiaprofenic acid, cicloprofen, diclofenac, benzydomine, theirpharmaceutically acceptable salts and mixtures thereof. All of these, aswell as acceptable dosage ranges, are described in the following: U.S.Pat. No. 4,749,720 to Sunshine et al. issued Jun. 7, 1988; U.S. Pat. No.4,749,721 to Sunshine et al. issued Jun. 7, 1988; U.S. Pat. No.4,749,722 to Sunshine et al. issued Jun. 7, 1988; U.S. Pat. No.4,749,723 to Sunshine et al. issued Jun. 7, 1988; U.S. Pat. No.4,749,711 to Sunshine et al. issued Jun. 7, 1988, U.S. Pat. No.4,749,697 to Sunshine et al. issued Jun. 7, 1988, U.S. Pat. No.4,783,465 to Sunshine et al., issued Nov. 8, 1988, U.S. Pat. No.4,619,934 to Sunshine et al., issued Oct. 28, 1986, U.S. Pat. No.4,840,962 to Sunshine et al. issued Jun. 20, 1989; U.S. Pat. No.4,906,625 to Sunshine et al. issued Mar. 6, 1990; U.S. Pat. No.5,025,019 to Sunshine et al. issued Jun. 18, 1991; U.S. Pat. No.4,552,899 to Sunshine et al. issued Nov. 12, 1985, Facts andComparisons, 1998, p. 242-260, all of which are incorporated byreference herein, in their entirety.

The decongestants used in the compositions of the present inventioninclude, for example, pseudoephedrine, phenylpropanolamine,phenylephrine, epinephrine, ephedrine, naphazoline, xylometazoline,oxymetazoline, propylhexedrine, tetrahydrozoline, their pharmaceuticallyacceptable salts, and mixtures thereof.

The expectorants (also known as mucolytic agents) used in the presentinvention include, for example, guaifenesin, iodinated glycerol,glyceryl guaiacolate, terpin hydrate, ammonium chloride,N-acetylcysteine and bromhexine, ambroxol, iodide, theirpharmaceutically acceptable salts, and mixtures thereof.

The antitussives used in the present invention include, for example,menthol (can also be used as an analgesic), dextromethorphan,chlophedianol, car-betapentane, caramiphen, noscapine, diphenhydramine,codeine, hydrocodone, hydromorphone, fominoben, benzonatate, theirpharmaceutically-acceptable salts, and mixtures thereof.

Examples of antihistamine agent used in the present invention includeboth sedating and non-sedating antihistamines, such as diphenhydramine,clemastine, chlorpheniramine, brompheniramine, dexchlorpheniramine,dexbrompheniramine, triprolidine, doxylamine, tripelennamine, heptadine,carbinoaxime, bromdiphenhydramine, hydroxyzine, pyrilamine, acrivastine,AHR-11325, phenindamine, astemizole, azatadine, azelastine, cetirizine,carebastine, efletirizine, mapinastine, ebastine, fexofenadine,ketotifen, Iodoxine, loratadine, descarboethoxyloratadine,levocabastine, mequitazine, oxatomide, setastine, tazifyline,temelastine, terfenadine, tripelennamine, terfenadine carboxylate,phenyltoloxamine, pheniramine, antazoline, bilastine, bepotastinebesilate, rupatadine, emedastine, tecastemizole, epinastine,levocetirizine, mizolastine, noberastine, norastemizole, olopatadine,pharmaceutically acceptable salts thereof, pharmaceutically activemetabolites thereof, optically active isomers or racemates, and mixturesthereof. All of these antihistamines, as well as their acceptable dosageranges, are described in: U.S. Patents to Sunshine et al. listed aboveunder analgesics; Facts and Comparisons, 1998, p. 188-195, which isincorporated by reference herein in its entirety.

Antihistamines are commercially widely available. The invention includesembodiments wherein the antihistamine is azelastine, olopatadine,cetirizine, or loratadine. Azelastine(4-[(4-chlorophenyl)methyl]-2-(1-methylazepan-4-yl)-phthalazin-1-one) isan antihistamine and mast cell stabilizer commercially available asASTELIN (MedPointe Inc., Cranbury, N.J.; MEDA Pharmaceuticals, Solna,Sweden) and indicated for the treatment of hay fever, seasonalallergies, and allergic conjunctivitis. Olopatadine is also anantihistamine and is commercially available as PATANASE® (Alcon. Ft.Worth, Tex.). These drugs are administered as follows. The compositionsof the invention comprising these drugs can be administered according tothe dosing regimens below or other dosing regimens disclosed herein.

Dosing Regimen per Total Drug Drug Affected Delivered Generic Name BrandName Strength Eye per Day* Ketotifen Zaditor ® 0.025% w/v 1 drop0.02-0.04 mg Fumerate (Novartis) every 12 hours Olopatadine HClPatanol ®; 0.1%; 0.2% w/v 1-2 drops 0.08-0.16 mg Pataday ™ twice daily;(Alcon) 1 drop once daily Azelastine HCl Optivar ® 0.05% w/v 1 droptwice 0.03-0.06 mg (Meda) daily Epinastine HCl Elestat ® 0.05% w/v 1drop twice 0.04 mg* (Allergan) daily Emadastine Emadine ® 0.05% w/v 1drop four 0.08 mg* Difumerate (Alcon) times daily Levocabastine HClLivostin ® 0.05% w/v 1 drop four 0.06-0.12 mg (Novartis) times daily *Atypical volume of an eye drop has been found to range from 25 to 50 mcL.So if the volume is not specified in the product label, it was assumedfor the purposes of this chart that the volume is 40 mcL as indicated bya asterisk.

In some embodiments, the composition of the invention comprises a doseor unit dose of azelastine present at an amount of about 30 μg to about275 μg, about 65 mcg to about 1100 mcg, about 130 mcg to about 650 mcg,about 30 μg, about 65 μg, about 137 mcg, about 274 mcg, about 548 mcg,or about 1096 mcg.

In some embodiments, the composition of the invention comprises a doseor unit dose of olopatadine present at an amount of about 330 mcg toabout 5500 mcg, about 330 mcg to about 2660 mcg, about 660 mcg to about5320 mcg, about 660 mcg to about 2660 mcg, about 550 mcg to about 1330mcg, about 665 mcg, about 1330 mcg, about 1995 mcg, about 2660 mcg,about 3325 mcg, about 3990 mcg, about 4655 mcg, or about 5320 mcg.

In some embodiments, the composition of the invention comprises a doseor unit dose of cetirizine present at an amount of about 0.25 mg to 5.55mg, 0.25 mg to about 4.4 mg, 0.55 mg to 4.4 mg, 0.55 mg to 3.3 mg, 0.55mg to 2.2 mg, about 0.55 mg, about 1.1 mg, about 2.2 mg, about 3.3 mg,about 4.4 mg, or about 5.5 mg per unit dose.

Bronchodilators used in the invention include, for example, terbutalinesulfate, isoetharine, aminophylline, oxtriphylline, dyphylline,ethylnorepinephrine, isoproterenol, epinephrine, isoprenaline,metaproterenol, bitoterol, theophylline, albuterol, isoproterenol andphenylephrine bitartrate, bitolterol, ephedrine sulfate, pirbuterolacetate, pharmaceutically acceptable salts thereof, and mixturesthereof. All of these bronchodilators, as well as their acceptabledosage ranges, are described in Facts and Comparisons, 1998, p.173b-179e, which is incorporated by reference herein in its entirety.

Topical anesthetics include, for example, lidocaine, dibucaine,dyclonine, benzocaine, butamben, tetracaine, pramoxine, theirpharmaceutically-acceptable salts, and mixtures thereof. All of theseagents, as well as their acceptable dosage ranges, are described inFacts and Comparisons, 1998, p. 601-607, which is incorporated byreference herein in its entirety.

Sensory agents include, for example, coolants, salivating agents, andwarming agents. These agents are present in the compositions at a levelof from about 0.001% to about 10%, preferably from about 0.1% to about1%, by weight of the composition. Suitable cooling agents includecarboxamides, menthols, thymol, camphor, capsicum, phenol, eucalyptusoil, benzyl alcohol, salicyl alcohol, ethanol, clove bud oil, andhexylresorcinol, ketals, diols, and mixtures thereof. Coolants can beparamenthan carboxyamide agents such as N-ethyl-p-menthan-3-carboxamide(WS-3 supplied by Sterling Organics), taught by U.S. Pat. No. 4,136,163,issued Jan. 23, 1979, to Watson et al., which is incorporated herein byreference in its entirety. Another paramenthan carboxyamide agent isN,2,3-trimethyl-2-isopropylbutanamide, known as “WS-23”, and mixtures ofWS-3 and WS-23. Additional coolants are selected from menthol,3-1-menthoxypropane-1,2-diol, known as TK-10 supplied by TakasagoPerfumery Co., Ltd., Tokyo, Japan, menthone glycerol acetal known asMGA, manufactured by Haarmann and Reimer, menthyl lactate known asFrescolat™ manufactured by Haarmann and Reimer, and mixtures thereof.Additional cooling agents include cyclic sulphones and sulphoxides andothers, all of which are described in U.S. Pat. No. 4,032,661, toRowsell et al., which is herein incorporated by reference. The terms“menthol” and “menthyl” as used herein include dextro- and levoratotoryisomers of these compounds and racemic mixtures thereof. TK-10 isdescribed in detail in U.S. Pat. No. 4,459,425, to Amano et al. andincorporated herein by reference.

Salivating agents include Jambu™ manufactured by Takasago Perfumery Co.,Ltd., Tokyo, Japan. Warming agents include capsicum and nicotinateesters, such as benzyl nicotinate.

Miscellaneous respiratory agents include, for example, leukotrienereceptor antagonists such as zafirlukast, zileuton; nasal inhalantproducts such as corticosteroids, other steroids, beclomethasone,flunisolide, triamcinolone; mucolytics such as acetylcysteine;anticholinergics such as ipratropium bromide; cromolyn sodium,nedocromil sodium; surfactants; and mixtures thereof. These agents canbe present in the compositions at a level of from about 0.001% to about10%, or from about 0.1% to about 5% by weight of the composition.

Antimicrobial agents can also be present. Such agents can include, butare not limited to, triclosan, 5-chloro-2-(2,4-dichlorophenoxy)-phenol,as described in The Merck Index, 11th ed. (1989), pp. 1529 (entry no.9573) in U.S. Pat. No. 3,506,720, and in European Patent Application No.0,251,591 of Beecham Group, PLC, published Jan. 7, 1988; chlorhexidine(Merck Index, no. 2090), alexidine (Merck Index, no. 222; hexetidine(Merck Index, no. 4624); sanguinarine (Merck Index, no. 8320);benzalkonium chloride (Merck Index, no. 1066); salicylanilide (MerckIndex, no. 8299); domiphen bromide (Merck Index, no. 3411);cetylpyridinium chloride (CPC) (Merck Index, no. 2024;tetradecylpyridinium chloride (TPC); N-tetradecyl-4-ethylpyridiniumchloride (TDEPC); octenidine; delmopinol, octapinol, and otherpiperidino derivatives; nicin preparations; zinc/stannous ion agents;antibiotics such as augmentin, amoxicillin, tetracycline, doxycycline,minocycline, and metronidazole; nystatin, tannic acid (forms protectivefilm over cold sores, fever blisters, and canker sores), clotrimazole,carbamide peroxide, amlexanox (indicated for treatment of aphthousulcers); and analogs and salts of the above antimicrobial antiplaqueagents. The antimicrobial agents generally comprise from about 0.1% toabout 5% by weight of the compositions of the present invention.

Exemplary suitable antiinfective, antibiotic and antifungal compoundsfor use in combination in a formulation of the invention are listed inthe table below. A combination composition of the invention can compriseone or more corticosteroids and one or more other therapeutic agents andcan be administered according to the dosing regimens below or otherdosing regimens herein.

Generic Name Brand Name Class Dosing Range Amikacin AmikinAminoglycoside 50-500 mg Amphotericin B Fungizone Antifungal 2.5-45 mgAzithromycin Zithromax Macrolide 50-400 mg Aztreonam Azactam Monobactam250-1000 mg Cefazolin Ancef, Kefzol Cephlasporin 250-1000 mg (Gen I)Cefepime Maxipime Cephlasporin 125-1000 mg (Gen IV) Cefonicid MoniacidCephlasporin 250-1000 mg (Gen II) Cefoperazone Cefobid Cephlasporin250-1000 mg (Gen III) Cefotaxime Claforan Cephlasporin 250-1000 mg (GenIII) Cefotetan Cefotan Cephlasporin 250-1000 mg (Cephamycin) CefoxitinMefoxin Cephlasporin 250-1000 mg (Cephamycin) Ceftazidime Fortaz, CeptazCephlasporin 250-1000 mg (Gen III) Ceftizoxime Cefizox Cephlasporin250-1000 mg (Gen III) Ceftriaxone Rocephin Cephlasporin 250-1000 mg (GenIII) Cefuroxime Ceftin Cephlasporin 100-600 mg (Gen II) CephapirinCefadyl Cephlasporin 250-1000 mg (Gen I) Ciprofloxacin Cipro Quinolone25-200 mg Clindamycin Cleocin Lincosamide 50-600 mg DoxycyclineVibramycin Tetracycline 10-100 mg Fluconazole Diflucan Antifungal12.5-150 mg Gentamycin Garamycin Aminoglycoside 10-200 mg ItraconazoleSporanox Antifungal 12.5-150 mg Levofloxacin Levaquin Quinolone 40-200mg Meropenem Merrin Carbapenem 200-750 mg Mezlocillin Mezlin Penicillin300-1500 mg Miconazole Monistat Antifungal 12.5-300 mg Nafcilin NafcilPenicillin 100-1000 mg Ofloxacin Floxin Quinolone 25-200 mg PiperacillinPipracil Penicillin 100-1000 mg Rifampin Rifadin Miscellaneous 500-5000mg Ticarcillin + Timentin Penicillin 500-5000 mg Clavulanate TobramycinNebcin Aminoglycoside 10-200 mg Vancomycin Vancocin Antifungal 50-400 mg

Other suitable antifungal agents include butoconazole, econazole,oxiconazole, sulconazole, tioconazole, posaconazole, terconazole,tiniconazole, voriconazole, anidulafungin (LY303366, VER-002),micafungin (FK463), Echinocandins, Cyclic Peptide Antifungals,Triazoles, genaconazole, ravuconazole, TAK-456 and TAK-457, ZD0870,UR-9625, UR-9746, UR-975 1 and UR-9825, T-8581, CS-758, SS-750,Echinocandin B (A30912A), Cilofungin (LY 121 01 9), FR901379(echinocandin-type peptide, WF11899A), FR901469 (lipopeptidolactone),FR131535, FR203903, Aculeacin A-G, Mulundocandin, Sporiofungin,Pneumocandin A, S3 17941F1, Corynecandin, Mer-WF3010, Fusacandin,Arthrichitin, Furanocandin, Azalomycins, LY 329960, DB 289, aminocandin,naftifine, terbinafine, caspofungin, nystatin, flucytosine,griseofulvin, and mixtures thereof.

The amount and/or concentration of corticosteroid and/or othertherapeutically effective agent in a unit dose or dose of thecomposition can be as specified herein or as customarily present inknown dosage forms comprising the same drugs.

The corticosteroid and/or other therapeutically effective agent, ifpresent, can be administered to a subject in need thereof according to adosing regimen as described herein or as recognized in the art as beingsuitable for the treatment of a disease, disorder or symptomtherapeutically responsive to the corticosteroid and/or othertherapeutically effective agent.

Methods of the invention can further comprise administering anadditional therapeutically effective agent. In some embodiments, thecorticosteroid and additional therapeutically effective agent areadministered simultaneously, sequentially, or separately.

Dosing, use and administration of the therapeutic agents disclosedherein is generally intended to follow the guidelines set forth in thePhysician's Desk Reference, 55^(th) Edition (Thompson Healthcare,Montvale, N.J., 2005) the relevant disclosure of which is herebyincorporated by reference. The amount of drug included in thecompositions of the present invention will be whatever amount istherapeutically effective and will depend upon a number of factors,including the identity and potency of the chosen drug, the disorderbeing treated, the health of the subject being treated and other suchfactors common to the pharmaceutical industry for prescription of drugsto a subject. The drugs will generally be administered according totheir known dosing regimens such as those disclosed in thePharmaceutical Desk Reference or those recognized as suitable by theFood and Drug Administration (USA), European Medicines Agency (Europe),National Institute of Health Sciences (Japan), and NationalAdministration of Drugs, Food, and Medical Technology (AdministraciónNacional de Medicamentos, Alimentos y Tecnología Médica, Argentina).

Non-limiting exemplary compositions of the invention comprising acorticosteroid and another active agent can comprise the followingcomponents.

FORM. Corticosteroid (A) Other Active Ingredient (B) I BudesonideOlopatadine* II Budesonide Azelastine* III Budesonide Azithromycin IVBudesonide Voriconazole V Budesonide Azithromycin and voriconazole VIMometasone furoate Azelastine* VII Mometasone furoate Olopatadine* VIIIMometasone furoate Azithromycin IX Fluticasone Loratadine proprionate XFluticasone Desloratadine proprionate XI Fluticasone Cetirizine*propionate XII Fluticasone Azelastine* propionate XIII FluticasoneOlopatadine* propionate XIV Fluticasone furoate Azelastine* XVFluticasone furoate Olopatadine* XVI Ciclesonide Azelastine* XVIICiclesonide Olopatadine* *denotes use as its salt, e.g. hydrochloridesalt, or free base

A combination formulation of the invention can comprise one or morecorticosteroids and one or more second therapeutic (active) agentsselected from azithromycin, clinafloxacin, gemifloxacin (Factive®),moxifloxacin (Avelox®), gatifloxacin (Tequin®, Zymar®), sitafloxacin,roxithromycin, norfloxacin, cetirizine hydrochloride, desloratadine,fexofenadine hydrochloride, natamycin, fluconazole itraconazoleketoconazole, capsaicin, benzocaine, tetrahydrozoline hydrochloride,oxymetazoline HCl, epinephrine, zileuton, cromolyn sodium, triazolam, apharmaceutically acceptable salt thereof, and an isomer thereof.

A composition comprising a corticosteroid and another active agent canbe prepared according to the examples below. In some embodiments, theSAE-CD is present in an amount sufficient to solubilize thecorticosteroid and the other active agent. In other embodiments, theSAE-CD is present in an amount sufficient to solubilize thecorticosteroid or the other active agent.

Depending upon the other active agent used, it may or may not bindcompetitively against the corticosteroid with the SAE-CD. In someembodiments, the SAE-CD has a higher equilibrium binding constant forthe other active agent than it has for the corticosteroid. In someembodiments, the SAE-CD has a higher equilibrium binding constant forthe corticosteroid than it has for the other active agent. In someembodiments, the SAE-CD has approximately the same equilibrium bindingconstant for the other active agent as it has for the corticosteroid.Alternatively, the other active agent does not bind with the SAE-CD eventhough the corticosteroid does. Accordingly, the invention providesembodiments wherein, the SAE-CD solubilizes the corticosteroid, theother active agent, or a combination thereof. The invention alsoprovides embodiments wherein, the SAE-CD solubilizes at least a majorportion of the corticosteroid, the other active agent, or of each. Theinvention also provides embodiments wherein, the SAE-CD does notsolubilize the other active agent.

The molar ratio of SAE-CD to corticosteroid and SAE-CD to other activeagent can vary as needed to provide a combination formulation asdescribed herein. The SAE-CD is generally present in molar excess overthe corticosteroid, the other active agent, or both.

A composition of the invention can comprise SAE-CD, corticosteroid,aqueous liquid carrier, and an antihistamine. In some embodiments, thecomposition contains SAE-CD, budesonide, water (or aqueous buffer) andazelastine. Example 14 details the preparation of such a composition.Other solutions of azelastine in buffer with varying amounts of SAE-CD,in the absence of budesonide, were prepared and scanned by UVSpectrometer. The change in absorption as a function of SAE-CDconcentration was plotted and used to determine the equilibrium bindingconstant of azelastine with SAE-CD, according to the Benesi-Hildebrandequation. The equilibrium binding constant of azelastine with CAPTISOLwas found to be approximately 10,000 at pH 4.5. The binding constant forbudesonide under similar conditions was determined to be about 1000;therefore, azelastine will compete with budesonide, or anothercorticosteroid, for binding to SAE-CD. Accordingly, the amount of SAE-CDpresent can be increased to permit complete dissolution of both drugs.

The equilibrium binding constant of the corticosteroid can change when asecond active agent is present in a composition of the invention. Sinceazelastine hydrochloride (AZ-HCl) has an approximately 10-fold higherbinding constant for SBE-β-CD than does budesonide (BUD), the amount ofSBE-β-CD present in an aqueous composition of the three needs to besufficient to solubilize both drugs. Example 19 details a procedure fordetermination of the phase solubility of budesonide in the presence ofvarying amounts of azelastine. The results are depicted in FIGS. 11A(for SBE-β-CD) and 11B (for SBE-β-CD and SBE-γ-CD). FIG. 11A is a chartof the phase solubility of BUD as a function of AZ-HCl concentration insolution in the presence of 20-40 mM CAPTISOL. The data indicate thatthe concentration of BUD at saturated solubility decreases as theconcentration of AZ-HCl increases. FIG. 11B is a chart of the phasesolubility of BUD as a function of SBE-β-CD or SBE-γ-CD concentration insolution using various different concentrations of AZ-HCl (1.00-2.75mg.mL). The data indicate that the concentration of BUD at saturatedsolubility decreases as the concentration of AZ-HCl increases and thathigher concentrations of SBE-CD are required in order to dissolve theBUD as the concentration of AZ-HCl increases. Thus, increasing theamount of AZ-HCl in the solution decreases the overall solubility ofBUD. The equilibrium complex stability constant between azelastine andSBE-β-CD is surprisingly about 5-times greater than that betweenazelastine and SBE-γ-CD (˜10000 M-1 versus 2200 M⁻¹) while theequilibrium complex stability constant for budesonide with SBE-β-CD ishalf that of the equilibrium complex stability constant for budesonidewith SBE-γ-CD (i.e. 1000 M⁻¹ versus 2000 M⁻¹). Surprisingly, the nominalamount of SBE-β-CD required to solubilize a similar dose of budesonidein the presence of azelastine is greater than in the absence ofazelastine as well as greater than the increase required if thecyclodextrin was SBE-γ-CD. Therefore, it is advantageous to preparesolution compositions of these combinations using SBE-γ-CD due to theefficiency of interaction so as to require less of one SAExCD versusanother different SAEyCD to solubilize similar amounts of actives in thepresence of each other.

In some embodiments of the invention, the concentrations of budesonide,azelastine (free base or HCl salt), and SAE-CD (e.g. SBE-CD) in thecomposition are as follows:

a) budesonide is present at a concentration of about 0.627 mg/g (32mcg/51 mg), about 0.457 mg/mL (32 mcg/70 mcL), 0.320 mg/mL (32 mcg/100mcL), about 0.320 mg/g (32 mcg/100 mg), from 0.04 mg/mL to 2 mg/mL, orfrom 0.04 mg/mL to 1 mg/mL;

b) azelastine is present at a concentration of about 0.5 to about 10mg/mL, about 0.5 to about 6 mg/mL, about 1 to about 5 mg/mL, about 1 toabout 3 mg/mL, about 2 to about 3 mg/mL, about 2.5 to about 3 mg/mL,about 2.75 mg/mL about 0.137 mg/51 mg, about 0.137 mg/0.137 mL, about0.137 mg/0.050 mL, about 0.137 mg/0.070 mL, about 0.137 mg/0.1 mL, orabout 1 mg/mL to 10 mg/mL (0.137 mg/0.020 mL); and/or

c) SAE-CD is present at a concentration of about 100 mg/mL, about 10 toabout 500 mg/mL, or about 10 to about 500 mg/g.

In some embodiments, the concentrations of budesonide, azelasatine andSAE-CD in the composition are as set forth in the table below.

[budesonide] [azelastine] [SBE-CD] 32 mcg/51 mg of 137 mcg/51 mg of 7mg/51 mg composition composition 32 mcg/70 mcL of 137 mcg/70 mcL of 7mg/70 mcL composition composition 32 mcg/100 mg of 137 mcg/100 mg of 7mg/100 mg composition composition 0.04 to 2 mg/mL of 1 to 10 mg/mL of 10to 500 mg/mL of composition composition composition (or per g ofcomposition)

In some embodiments of the invention, the concentrations of budesonide,olopatadine (free base or HCl salt), and SAE-CD (e.g. SBE-CD) in thecomposition are as follows:

a) budesonide is present at a concentration of about 0.627 mg/g (32mcg/51 mg), about 0.457 mg/mL (32 mcg/70 mcL), 0.320 mg/mL (32 mcg/100mcL), about 0.320 mg/g (32 mcg/100 mg), from 0.04 mg/mL to 2 mg/mL, orfrom 0.04 mg/mL to 1 mg/mL;

b) olopatadine is present at a concentration of about 0.5 to about 15mg/mL, about 1 to about 10 mg/mL, about 1 to about 15 mg/mL, about 5 toabout 10 mg/mL, about 6 to about 7 mg/mL, about 0.665 mg/0.10 mL, about0.665 mg/0.70 mL, about 0.665 mg/0.50 mL, 5.32 mg/0.2 mL, or about 6.5mg/5 mL; and/or

c) SAE-CD is present at a concentration of about 100 mg/mL, about 10 toabout 500 mg/mL, or about 10 to about 500 mg/g.

In some embodiments of the invention, the concentrations of budesonide,cetirizine (free base or HCl salt), and SAE-CD (e.g. SBE-CD) in thecomposition are as follows:

a) budesonide is present at a concentration of about 0.627 mg/g (32mcg/51 mg), about 0.457 mg/mL (32 mcg/70 mcL), 0.320 mg/mL (32 mcg/100mcL), about 0.320 mg/g (32 mcg/100 mg), from 0.04 mg/mL to 2 mg/mL, orfrom 0.04 mg/mL to 1 mg/mL;

b) cetirizine is present at a concentration of about 0.25 to about 4.4mg/mL, about 0.55 to about 4.4 mg/mL, about 1.1 to about 4.4 mg/mL,about 1.1 to about 2.2 mg/mL, about 1 to about 25 mg/mL, about 2 toabout 24 mg/mL, about 5 to about 20 mg/mL, about 7 to about 15 mg/mL,about 10 to about 12 mg/mL, about 1.1 mg/0.1 mL, about 1.1 mg/0.05 mL,about 1.1 mg/0.70 mL, about 1.1 mg/0.2 mL, or about 2.2 mg/5 mL; and/or

c) SAE-CD is present at a concentration of about 100 mg/mL, about 10 toabout 500 mg/mL, or about 10 to about 500 mg/g.

In some embodiments of the invention, the concentrations of mometasonefuroate, olopatadine (free base or HCl salt), and SAE-CD (e.g. SBE-CD)in the composition are as follows:

a) mometasone furoate is present at a concentration of about 0.5 mg/mL(50 mcg/100 mcL), about 0.71 mg/mL (50 mcg/70 mcL), about 1.0 mg/mL (50mcg/100 mcL), about 1.0 mg/mL (200 mcg/200 mcL), or about 0.1 mg/mL (500mcg/5000 mcL);

b) olopatadine is present at a concentration of about 0.5 to about 15mg/mL, about 1 to about 10 mg/mL, about 1 to about 15 mg/mL, about 5 toabout 10 mg/mL, about 6 to about 7 mg/mL, about 0.665 mg/0.10 mL, about0.665 mg/0.70 mL, about 0.665 mg/0.50 mL, 5.32 mg/0.2 mL, or about 6.5mg/5 mL; and/or

c) SAE-CD is present at a concentration of about 300 mg/mL, about 10 toabout 500 mg/mL, or about 10 to about 500 mg/g.

In some embodiments of the invention, the concentrations of fluticasonepropionate, cetirizine (free base or HCl salt), and SAE-CD (e.g. SBE-CD)in the composition are as follows:

a) fluticasone propionate is present at a concentration of about 0.5mg/mL (50 mcg/100 mcL), about 0.71 mg/mL (50 mcg/70 mcL), about 1.0mg/mL (50 mcg/100 mcL), about 1.0 mg/mL (200 mcg/200 mcL), or about 0.1mg/mL (500 mcg/5000 mcL);

b) cetirizine is present at a concentration of about 0.55 to about 4.4mg/mL, about 1.1 to about 4.4 mg/mL, about 1.1 to about 2.2 mg/mL, about1 to about 25 mg/mL, about 2 to about 24 mg/mL, about 5 to about 20mg/mL, about 7 to about 15 mg/mL, about 10 to about 12 mg/mL, about 1.1mg/0.1 mL, about 1.1 mg/0.05 mL, about 1.1 mg/0.70 mL, about 1.1 mg/0.2mL, or about 2.2 mg/5 mL; and/or

c) SAE-CD is present at a concentration of about 300 mg/mL, about 10 toabout 500 mg/mL, or about 10 to about 500 mg/g.

Embodiments of the present invention allow for combination compositions(those containing two or more active agents (therapeutic agents)) to beprepared in a variety of ways:

1) Mixing ready to use solutions of a second therapeutic agent with aready to use solution of a corticosteroid in SAE-CD;

2) Mixing ready to use solutions of a second therapeutic agent with aconcentrated solution of a corticosteroid dissolved using SAE-CD;

3) Mixing a ready to use solution of a second therapeutic agent withsubstantially dry SAE-CD and a substantially dry corticosteroid;

4) Mixing a ready to use solution of a second therapeutic agent with asubstantially dry mixture of SAE-CD and a corticosteroid or moreconveniently a pre-measured amount of the mixture in a unit containersuch as a capsule (empty a capsule into ready to use solution);

5) Mixing a ready to use solution of a corticosteroid such as budesonidewith a substantially dry second therapeutic agent; or

6) Dissolving a substantially dry second therapeutic agent and asubstantially dry SAE-CD plus a substantially dry corticosteroid.

The materials used herein can be used in micronized or non-micronizedform and crystalline, polymorphic or amorphous form. This isparticularly true of the corticosteroids and other active ingredients.

It is well understood by those of ordinary skill in the art that theabove solutions or powders can optionally contain other ingredients suchas buffers and/or tonicity adjusters and/or antimicrobials and/oradditives or other such excipients as set forth herein or as presentlyused in nasally administered liquid formulations.

A corticosteroid-responsive disease, symptom or disorder is one whereina subject suffering from such will receive a clinical benefit afteradministration of a corticosteroid according to the invention. A type ofcorticosteroid-responsive disease, symptom or disorder is any allergicand/or inflammatory disease, symptom or disorder. Exemplary ones includenasal symptom, non-nasal symptom, ocular symptom, acute or chronicrhinitis, nasal polyps, post surgical polyps, obstructive sleep apnea,Eustachian tube dysfunction, serous otitis media, sleep disturbances,daytime somnolesence, snoring, cluster headache, nasal furuncles,epistaxis, wounds of the nasal or sinunasal mucosa, dry nose syndrome,nasal bleeding, herpes, sarcoidosis, fibrosis, cancer, autoimmunereaction, or a combination thereof.

In some embodiments, acute or chronic rhinitis is selected from thegroup consisting of allergic rhinitis, seasonal allergic rhinitis,perennial allergic rhinitis, perennial non-allergic rhinitis, bacterialrhinitis, fungal rhinitis, viral rhinitis, atrophic rhinitis, grasspollen rhinitis, have fever, blocked nose, nasal congestion, vasomotorrhinitis, or a combination thereof.

In some embodiments, the nasal symptom is rhinorrhea, nasal congestion,nasal itchiness, sneezing, nasal obstruction or a combination thereof.In some embodiments, the non-nasal symptom is itchy/gritty eyes,tearing/watery eyes, red/burning eyes, itchy ears and palate, or acombination thereof.

In some embodiments, the invention excludes a method of or system fortreating asthma, allergic asthma, rhinosinusitis, and/or sinusitis.

Conjunctivitis is an inflammation of the conjunctiva, the membranelining the external surface of the eye, and is most often caused by anallergic reaction. Allergic conjuctivitis is one of the most common eyeconditions in children and adults with symptoms including itching,stinging, burning, redness, tearing and swelling of the eyelids and thewhites of the eye. Allergic conjunctivitis is most often associated withallergic rhinitis (Hay Fever) and can be associated with asthma.

Allergic rhinitis is one of the most chronic atopic diseases that isassociated with considerable cost and co-morbidity. Allergic rhinitis isinitiated by an IgE-mediated response to allergens and results in aconsequent release of preformed mediators and cytokines, which induceinflammatory cell recruitment and their activation at the target organ.Seasonal allergic rhinitis (SAR), triggered by pollen from trees,grasses and weeds, is characterized by sneezing, nasal congestion, nasalitching, rhinorrhea, and pruritic, watery red eyes.

Animal dander, mold, dust, and dust mites can also trigger symptoms ofrhinitis. Non-allergic rhinitis can also be induced by viruses, andenvironmental factors such as toxins and tobacco smoke.

Corticosteroids can also be used to treat ocular conditions such as: (1)inflammatory conditions including conditions of the palpebral and bulbarconjunctiva, cornea, and anterior segment of the globe such as allergicconjunctivitis, acne rosacea, superficial punctate keratitis, herpeszoster keratitis, iritis, cyclitis, selected infective conjunctivitis;(2) corneal injuries including injury from chemical, radiation, orthermal burns or penetration by foreign bodies; and (3) ocular pain andburning/stinging following ocular surgery such as corneal refractivesurgery.

The compositions of the invention can generally have a storage shelflife of 6 months. In this case, shelf life is determined only as regardsthe increase in the amount of corticosteroid degradation by-products ora reduction in the amount of corticosteroid remaining in thecomposition. For example, for a composition having a shelf life of atleast six months, the composition will not demonstrate an unacceptableand substantial increase in the amount of degradants during the storageperiod of at least six months. The criteria for acceptable shelf-lifeare set as needed according to a given product and its storage stabilityrequirements. In other words, the amount of degradants in a compositionhaving an acceptable shelf-life will not increase beyond a predeterminedvalue during the intended period of storage. On the other hand, theamount of degradants of a composition having an unacceptable shelf-lifewill increase beyond the predetermined value during the intended periodof storage.

The method of Example 3 can be followed to determine the stability ofthe active agent in solution. The shelf-life can be defined as the timeto loss of less than about 10%, less than about 5%, less than about 3%,less than about 2% or less than about 1% potency. Under the conditionstested, the loss of potency was first order. The shelf life of aCAPTISOL-ENABLED Budesonide Nasal Solution (a solution comprisingbudesonide and SBE7-O-CD) is greater than about 3 years at a pH between4 and 5, i.e. about 90 months at pH 4.0 and about 108 months at pH 5.0without the need to add any other stabilizers, such as EDTA, in water inthe presence of about 5% wt./vol. SAE-CD.

SAE-CD is also capable of stabilizing the isomers of budesonide todifferent extents. SBE7-β-CD stabilized both R- and S-isomers ofbudesonide in solutions at both pH 4 and 6. The with/without CAPTISOLratio of rate constants was much less than 1 at all temperatures.SBE7-β-CD had a greater effect on the stability of both the R andS-isomer at pH 6 than at pH 4. At a given temperature the ratio of rateconstants with/without SBE7-β-CD was less at pH 6 than at pH 4. AlthoughSBE7-β-CD stabilized both isomers, the S-isomer appears to be stabilizedto an even greater extent than the R. At all temperatures and pHstested, the ratio of rate constants with/without SBE7-β-CD was lower forthe S isomer. The degree of stabilization affected by SBE7-β-CD at 60°C. is greater than at 80° C. An even greater degree of stabilizationwould be expected at 40° C. and/or room temperature (20-30° C.).Accordingly a solution comprising SAE-CD and budesonide is stable at apH from 4 to 6, from 4 to 5, or about 4.5.

SBE7-β-CD also significantly reduced the photode composition ofbudesonide. The loss of budesonide was first order and independent ofpH.

SAE-CD is also capable of stabilizing a second active agent included inthe composition. Example 16 details a procedure for evaluating thestability of azelastine in the presence of SAE-CD at varyingtemperatures and in solutions of different pH's. The results aredepicted in FIGS. 10A to 10C. The SAE-CD stabilized the azelastine forthe period of sixteen weeks regardless of the temperature or pH of thesolution. The lower the temperature, the greater the stabilization. Ofthe three pH values evaluated, the greatest stabilization was observedat pH 5. Accordingly, a solution comprising SAE-CD and azelastine ismost stable at a pH from 4 to 6 or from 4.5 to 5.5.

The composition of the invention can be provided as a powder adapted toform an aqueous solution for nasal, non-nasal and/or ophthalmicadministration. The powder can also be adapted for administration with apowder-administering device. The powder can instead comprise anadmixture of a solid derivatized cyclodextrin and solid corticosteroidand, optionally, at least one solid pharmaceutical excipient, such thata major portion of the active agent is not complexed with thederivatized cyclodextrin prior to reconstitution of the admixture withan aqueous carrier. Alternatively, the composition can comprise a solidmixture comprising the inclusion complex of a derivatized cyclodextrinand an active agent, wherein a major portion of the active agent iscomplexed with the derivatized cyclodextrin prior to reconstitution ofthe solid mixture with an aqueous carrier.

A powder composition of the invention can be prepared according to anyof the following processes. A liquid composition of the invention isfirst prepared, then a solid is formed by lyophilization(freeze-drying), spray-drying, spray freeze-drying, antisolventprecipitation, various processes utilizing supercritical or nearsupercritical fluids, or other methods known to those of ordinary skillin the art to make a solid for reconstitution. Examples 25, 26, 27, 29details a method for the preparation of a lyophilized solid compositioncomprising corticosteroid and SAE-CD by lyophilization of a liquidcomposition or formulation of the invention.

A liquid vehicle (carrier) included in a formulation of the inventioncomprises a pharmaceutically acceptable aqueous liquid carrier, such aswater or buffer, aqueous alcohol, propylene glycol, glycerin,poly(ethylene glycol), poloxamer, povidone, polyol (such as sorbitol),aqueous organic solvent or a combination thereof. Example 30 details thepreparation of a liquid formulation comprising 20% w/v SAE-CD,corticosteroid, water and ethanol (0-5%). Increasing the concentrationof the ethanol in the liquid resulted in a decrease in the maximumsaturated solubility of the corticosteroid. For nasal administration, anaqueous liquid carrier can be aqueous saline (which generally containssodium chloride as the salt, and is fully described in Remington'sPharmaceutical Sciences, 19.sup.th edition (1995) p. 1502, which isherein incorporated by reference). The salt can be present in thesolution at a level of about 0.01% to about 2%, preferably from about0.5% to about 1.0% by weight of solution. Suitable nontoxicpharmaceutically acceptable nasal carriers are known to those skilled inthe art. The choice of a suitable carrier will depend on the exactnature of the particular nasal dosage form required, e.g., whether theactive agent is to be formulated into a nasal solution (for use as dropsor as a spray), a nasal ointment, a nasal gel or another nasal form.

The compositions of the invention can include a preservative,antioxidant, buffering agent, acidifying agent, alkalizing agent,colorant, solubilizing agent, solubility-enhancing agent,complexation-enhancing agent, diluent, electrolyte, glucose, stabilizer,bulking agent, antifoaming agent, oil, emulsifying agent,cryoprotectant, plasticizer, flavors, sweeteners, taste-masking agent,tonicity modifier, surface tension modifier, surfactant, viscositymodifier, density modifier, volatility modifier, saline, otherexcipients known by those of ordinary skill in the art for use inpreserved formulations, or a combination thereof.

As used herein, the term “alkalizing agent” is intended to mean acompound used to provide alkaline medium, such as for product stability.Such compounds include, by way of example and without limitation,ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine,potassium hydroxide, sodium borate, sodium carbonate, sodiumbicarbonate, sodium hydroxide, triethanolamine, diethanolamine, organicamine base, alkaline amino acids and trolamine and others known to thoseof ordinary skill in the art.

As used herein, the term “acidifying agent” is intended to mean acompound used to provide an acidic medium for product stability. Suchcompounds include, by way of example and without limitation, aceticacid, acidic amino acids, citric acid, fumaric acid and other alphahydroxy acids, hydrochloric acid, ascorbic acid, phosphoric acid,sulfuric acid, tartaric acid and nitric acid and others known to thoseof ordinary skill in the art.

Inclusion of a preservative in the solution is optional, since theformulation is self-preserved by SAE-CD depending upon its concentrationin solution. If a conventional preservative is included in thecomposition, the corticosteroid, such as budesonide, can have a greaterbinding with the SAE-CD than does a conventional preservative.Nonetheless, a preservative can be further included in the formulationif desired. Preservatives can be used to inhibit microbial growth in thecompositions. The amount of preservative is generally that which isnecessary to prevent microbial growth in the composition for a storageperiod of at least six months. As used herein, a preservative is acompound used to at least reduce the rate at which bioburden increases,but preferably maintains bioburden steady or reduces bioburden aftercontamination has occurred. Such compounds include, by way of exampleand without limitation,3-(trimethoxysilyl)propyldimethyloctadecylammonium chloride,stearyldimethylbenzyl-ammonium chloride,6-acetoxy-2,4-dimethylmetadioxane, alkali metal sorbates and mixtures,ammonium sorbate, BAC, benzalkonium chloride, benzethonium chloride,benzoic acid (and salts), benzyl alcohol, boric acid, bronopol, butylparabens, C.sub.16 benzalkonium halide compounds, cetrimide,cetyldimethylbenzylammonium chloride, cetylpyridinium bromide,cetylpyridinium chloride, chlorbutanol, chlorhexidine, chlorine dioxide,chlorite components, Chlorobutanol, chlorocresol, chlorohexidinegluconate, chlorohexidine hydrochloride, cresol,distearyldimethylammonium chloride, dodecylguanidine, dodecylguanidinehydrochloride, domiphen bromide, ethanol, ethyl parabens, guanidines,lauroylisoquinolium bromide, metacresol, Methylparaben, myristylgammapicolinium chloride, paraben mixtures, phenol, phenol derivative,phenoxyethanol, phenylethanol, phenylmercuric acetate, phenylmercuricnitrate, phenylmercuric salts, polyhexmethylenebiguanidinehydrochloride, polymeric quaternary ammonium compounds, potassiumsorbate, propylparaben, quaternary ammonium alkylene glycol phospholipidderivatives, quaternary ammonium salts, propyl parabens, sodium sorbate,sorbic acid (and salts), stearylpentaethoxyammonium chloride,stearyltolylmethyl-ammonium chloride, sulfites inorganic, thiomersal,thymol, and others known to those of ordinary skill in the art.

As used herein, the term “antioxidant” is intended to mean an agent thatinhibits oxidation and thus is used to prevent the deterioration ofpreparations by the oxidative process. Such compounds include, by way ofexample and without limitation, acetone, potassium metabisulfite,potassium sulfite, ascorbic acid, ascorbyl palmitate, citric acid,butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorousacid, monothioglycerol, propyl gallate, sodium ascorbate, sodiumcitrate, sodium sulfide, sodium sulfite, sodium bisulfite, sodiumformaldehyde sulfoxylate, thioglycolic acid, EDTA, pentetate, sodiummetabisulfite, and others known to those of ordinary skill in the art.

As used herein, the term “buffering agent” is intended to mean acompound used to resist change in pH upon dilution or addition of acidor alkali. Buffers are used in the present compositions to adjust the pHto a range of between about 2 and about 8, about 3 to about 7, or about4 to about 5. Such compounds include, by way of example and withoutlimitation, acetic acid, sodium acetate, adipic acid, benzoic acid,sodium benzoate, boric acid, sodium borate, citric acid, glycine, maleicacid, monobasic sodium phosphate, dibasic sodium phosphate, HEPES,lactic acid, tartaric acid, potassium metaphosphate, potassiumphosphate, monobasic sodium acetate, sodium bicarbonate, tris, sodiumtartrate and sodium citrate anhydrous and dihydrate and others known tothose of ordinary skill in the art. Other buffers include citricacid/phosphate mixture, acetate, barbital, borate, Britton-Robinson,cacodylate, citrate, collidine, formate, maleate, Mcllvaine, phosphate,Prideaux-Ward, succinate, citrate-phosphate-borate (Teorell-Stanhagen),veronal acetate, MES (2-(N-morpholino)ethanesulfonic acid), BIS-TRIS(bis(2-hydroxyethyl)imino-tris(hydroxymethyl)methane), ADA(N-(2-acetamido)-2-iminodiacetic acid), ACES(N-(carbamoylmethyl)-2-aminoethanesulfonaic acid), PIPES(piperazine-N,N′-bis(2-ethanesulfonic acid)), MOPSO(3-(N-morpholino)-2-hydroxypropanesulfonic acid), BIS-TRIS PROPANE(1,3-bis(tris(hydroxymethyl)methylamino)propane), BES(N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonaic acid), MOPS(3-(N-morpholino)propanesulfonic acid), TES(N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid), HEPES(N-(2-hydroxyethyl)piperazine-N′-(2-ethanesulfonic acid), DIPSO(3-(N,N-bis(2-hydroxyethyl)amino)-2-hydroxypropanesulfonic acid), MOBS(4-(N-morpholino)-butanesulfonic acid), TAPSO(3-(N-tris(hydroxymethyl)methylamino)-2-hydroxypropanesulfonic acid),TRIZMA™ (tris(hydroxymethylaminomethane), HEPPSO(N-(2-hydroxyethyl)piperazine-N′-(2-hydroxypropanesulfonic acid), POPSO(piperazine-N,N′-bis(2-hydroxypropanesulfonic acid)), TEA(triethanolamine), EPPS(N-(2-hydroxyethyl)piperazine-N′-(3-propanesulfonic acid), TRICINE(N-tris(hydroxymethyl)methylglycine), GLY-GLY (glycylglycine), BICINE(N,N-bis(2-hydroxyethyl)glycine), HEPBS(N-(2-hydroxyethyl)piperazine-N′-(4-butanesulfonic acid)),TAPS(N-tris(hydroxymethyl)methyl-3-aminopropanesulfonic acid), AMPD(2-amino-2-methyl-1,3-propanediol), and/or any other buffers known tothose of skill in the art.

A complexation-enhancing agent can be added to the compositions of theinvention. When such an agent is present, the ratio ofcyclodextrin/active agent can be changed. A complexation-enhancing agentis a compound, or compounds, that enhance(s) the complexation of theactive agent with the cyclodextrin. Suitable complexation enhancingagents include one or more pharmacologically inert water solublepolymers, hydroxy acids, and other organic compounds typically used inliquid formulations to enhance the complexation of a particular agentwith cyclodextrins.

Hydrophilic polymers can be used as complexation-enhancing,solubility-enhancing and/or water activity reducing agents to improvethe performance of formulations containing a cyclodextrin. Suitablepolymers are disclosed in Pharmazie (2001), 56(9), 746-747;International Journal of Pharmaceutics (2001), 212(1), 29-40;Cyclodextrin: From Basic Research to Market, International CyclodextrinSymposium, 10th, Ann Arbor, Mich., United States, May 21-24, 2000(2000), 10-15 (Wacker Biochem Corp.: Adrian, Mich.); PCT InternationalPublication No. WO 9942111; Pharmazie, 53(11), 733-740 (1998); Pharm.Technol. Eur., 9(5), 26-34 (1997); J. Pharm. Sci. 85(10), 1017-1025(1996); European Patent Application EP0579435; Proceedings of theInternational Symposium on Cyclodextrins, 9th, Santiago de Comostela,Spain, May 31-Jun. 3, 1998 (1999), 261-264 (Editor(s): Labandeira, J. J.Torres; Vila-Jato, J. L. Kluwer Academic Publishers, Dordrecht, Neth);S.T.P. Pharma Sciences (1999), 9(3), 237-242; ACS Symposium Series(1999), 737(Polysaccharide Applications), 24-45; Pharmaceutical Research(1998), 15(11), 1696-1701; Drug Development and Industrial Pharmacy(1998), 24(4), 365-370; International Journal of Pharmaceutics (1998),163(1-2), 115-121; Book of Abstracts, 216th ACS National Meeting,Boston, Aug. 23-27 (1998), CELL-016, American Chemical Society; Journalof Controlled Release, (1997), 44/1 (95-99); Pharm. Res. (1997) 14(11),S203; Investigative Opthalmology & Visual Science, (1996), 37(6),1199-1203; Proceedings of the International Symposium on ControlledRelease of Bioactive Materials (1996), 23 rd, 453-454; Drug Developmentand Industrial Pharmacy (1996), 22(5), 401-405; Proceedings of theInternational Symposium on Cyclodextrins, 8th, Budapest, Mar. 31-Apr. 2,(1996), 373-376. (Editor(s): Szejtli, J.; Szente, L. Kluwer: Dordrecht,Neth.); Pharmaceutical Sciences (1996), 2(6), 277-279; European Journalof Pharmaceutical Sciences, (1996) 4(SUPPL.), S144; Third EuropeanCongress of Pharmaceutical Sciences Edinburgh, Scotland, UK Sep. 15-17,1996; Pharmazie, (1996), 51(1), 39-42; Eur. J. Pharm. Sci. (1996),4(Suppl.), S143; U.S. Pat. No. 5,472,954 and U.S. Pat. No. 5,324,718;International Journal of Pharmaceutics (Netherlands), (Dec. 29, 1995)126, 73-78; Abstracts of Papers of the American Chemical Society, (02APR 1995) 209(1), 33-CELL; European Journal of Pharmaceutical Sciences,(1994) 2, 297-301; Pharmaceutical Research (New York), (1994) 11(10),S225; International Journal of Pharmaceutics (Netherlands), (Apr. 11,1994) 104, 181-184; and International Journal of Pharmaceutics (1994),110(2), 169-77, the entire disclosures of which are hereby incorporatedby reference.

Other suitable polymers are well-known excipients commonly used in thefield of pharmaceutical formulations and are included in, for example,Remington's Pharmaceutical Sciences, 18th Edition, Alfonso R. Gennaro(editor), Mack Publishing Company, Easton, Pa., 1990, pp. 291-294;Alfred Martin, James Swarbrick and Arthur Commarata, Physical Pharmacy.Physical Chemical Principles in Pharmaceutical Sciences, 3rd edition(Lea & Febinger, Philadelphia, Pa., 1983, pp. 592-638); A. T. Florenceand D. Altwood, (Physicochemical Principles of Pharmacy, 2nd Edition,MacMillan Press, London, 1988, pp. 281-334. The entire disclosures ofthe references cited herein are hereby incorporated by references. Stillother suitable polymers include water-soluble natural polymers,water-soluble semi-synthetic polymers (such as the water-solublederivatives of cellulose) and water-soluble synthetic polymers. Thenatural polymers include polysaccharides such as insulin, pectin, alginderivatives (e.g. sodium alginate) and agar, and polypeptides such ascasein and gelatin. The semi-synthetic polymers include cellulosederivatives such as methylcellulose, hydroxyethylcellulose,hydroxypropyl cellulose, their mixed ethers such as hydroxypropylmethylcellulose and other mixed ethers such as hydroxyethylethylcellulose and hydroxypropyl ethylcellulose, hydroxypropylmethylcellulose phthalate and carboxymethylcellulose and its salts,especially sodium carboxymethylcellulose. The synthetic polymers includepolyoxyethylene derivatives (polyethylene glycols) and polyvinylderivatives (polyvinyl alcohol, polyvinylpyrrolidone and polystyrenesulfonate) and various copolymers of acrylic acid (e.g. carbomer). Othernatural, semi-synthetic and synthetic polymers not named here which meetthe criteria of water solubility, pharmaceutical acceptability andpharmacological inactivity are likewise considered to be within theambit of the present invention.

An emulsifying agent is intended to mean a compound that aids theformation of an emulsion. An emulsifier can be used to wet thecorticosteroid and make it more amenable to dissolution. Emulsifiers foruse herein include, but are not limited to, polyoxyethylene sorbitanfatty esters or polysorbates, including, but not limited to,polyethylene sorbitan monooleate (Polysorbate 80), polysorbate 20(polyoxyethylene (20) sorbitan monolaurate), polysorbate 65(polyoxyethylene (20) sorbitan tristearate), polyoxyethylene (20)sorbitan mono-oleate, polyoxyethylene (20) sorbitan monopalmitate,polyoxyethylene (20) sorbitan monostearate; lecithins; alginic acid;sodium alginate; potassium alginate; ammonium alginate; calciumalginate; propane-1,2-diol alginate; agar; carrageenan; locust bean gum;guar gum; tragacanth; acacia; xanthan gum; karaya gum; pectin; amidatedpectin; ammonium phosphatides; microcrystalline cellulose;methylcellulose; hydroxypropylcellulose; hydroxypropylmethylcellulose;ethylmethylcellulose; carboxymethylcellulose; sodium, potassium andcalcium salts of fatty acids; mono- and di-glycerides of fatty acids;acetic acid esters of mono- and di-glycerides of fatty acids; lacticacid esters of mono- and di-glycerides of fatty acids; citric acidesters of mono- and di-glycerides of fatty acids; tartaric acid estersof mono- and di-glycerides of fatty acids; mono- and diacetyltartaricacid esters of mono- and di-glycerides of fatty acids; mixed acetic andtartaric acid esters of mono- and di-glycerides of fatty acids; sucroseesters of fatty acids; sucroglycerides; polyglycerol esters of fattyacids; polyglycerol esters of polycondensed fatty acids of castor oil;propane-1,2-diol esters of fatty acids; sodium stearoyl-2-lactylate;calcium stearoyl-2-lactylate; stearoyl tartrate; sorbitan monostearate;sorbitan tristearate; sorbitan monolaurate; sorbitan monooleate;sorbitan monopalmitate; extract of quillaia; polyglycerol esters ofdimerised fatty acids of soya bean oil; oxidatively polymerised soyabean oil; and pectin extract.

As used herein, the term “stabilizer” is intended to mean a compoundused to stabilize the therapeutic agent against physical, chemical, orbiochemical process that would reduce the therapeutic activity of theagent. Suitable stabilizers include, by way of example and withoutlimitation, albumin, sialic acid, creatinine, glycine and other aminoacids, niacinamide, sodium acetyltryptophonate, zinc oxide, sucrose,glucose, lactose, sorbitol, mannitol, glycerol, polyethylene glycols,sodium caprylate, sodium saccharin and other known to those of ordinaryskill in the art.

As used herein, the term “viscosity modifier” is intended to mean acompound or mixture of compounds that can be used to adjust theviscosity of an aqueous liquid composition of the invention. Theviscosity modifier can increase or decrease the viscosity. Suitableviscosity modifiers include HPMC, CMC (sodium carboxymethylcellulose),glycerin, PEG and others recognized by artisans in the field. In someembodiments, the composition excludes HPMC.

As used herein, the term “tonicity modifier” is intended to mean acompound or compounds that can be used to adjust the tonicity of theliquid formulation. Suitable tonicity modifiers include glycerin,lactose, mannitol, dextrose, sodium chloride, sodium sulfate, sorbitol,trehalose and others known to those of ordinary skill in the art. Othertonicity modifiers include both inorganic and organic tonicity adjustingagents. Tonicity modifiers include, but are not limited to, ammoniumcarbonate, ammonium chloride, ammonium lactate, ammonium nitrate,ammonium phosphate, ammonium sulfate, ascorbic acid, bismuth sodiumtartrate, boric acid, calcium chloride, calcium disodium edetate,calcium gluconate, calcium lactate, citric acid, dextrose,diethanolamine, dimethylsulfoxide, edetate disodium, edetate trisodiummonohydrate, fluorescein sodium, fructose, galactose, glycerin, lacticacid, lactose, magnesium chloride, magnesium sulfate, mannitol,polyethylene glycol, potassium acetate, potassium chlorate, potassiumchloride, potassium iodide, potassium nitrate, potassium phosphate,potassium sulfate, proplyene glycol, silver nitrate, sodium acetate,sodium bicarbonate, sodium biphosphate, sodium bisulfite, sodium borate,sodium bromide, sodium cacodylate, sodium carbonate, sodium chloride,sodium citrate, sodium iodide, sodium lactate, sodium metabisulfite,sodium nitrate, sodium nitrite, sodium phosphate, sodium propionate,sodium succinate, sodium sulfate, sodium sulfite, sodium tartrate,sodium thiosulfate, sorbitol, sucrose, tartaric acid, triethanolamine,urea, urethan, uridine and zinc sulfate. In some embodiments, thetonicity of the liquid formulation approximates the tonicity of thetissues in the respiratory tract.

An osmotic agent can be used in the compositions to enhance the overallcomfort to the patient upon delivery of the corticosteroid composition.Osmotic agents can be added to adjust the tonicity of SAE-CD containingsolutions. Osmolality is related to concentration of SAE-CD in water. AtSBE7-β-CD concentrations below about 11-13% w/v, the solutions arehypotonic or hypoosmotic with respect to blood and at SBE7-β-CDconcentrations above about 11-13% w/v the SBE7-β-CD containing solutionsare hypertonic or hyperosmotic with respect to blood. When red bloodcells are exposed to solutions that are hypo- or hypertonic, they canshrink or swell in size, which can lead to hemolysis. SBE-CD is lessprone to induce hemolysis than other derivatized cyclodextrins. Suitableosmotic agents include any low molecular weight water-soluble speciespharmaceutically approved for nasal delivery such as sodium chloride,lactose and glucose. The formulation of the invention can also includebiological salt(s), potassium chloride, or other electrolyte(s).

As used herein, the term “antifoaming agent” is intended to mean acompound or compounds that prevents or reduces the amount of foamingthat forms on the surface of the liquid formulation. Suitableantifoaming agents include dimethicone, simethicone, octoxynol, ethanoland others known to those of ordinary skill in the art.

As used herein, the term “bulking agent” is intended to mean a compoundused to add bulk to the lyophilized product and/or assist in the controlof the properties of the formulation during lyophilization. Suchcompounds include, by way of example and without limitation, dextran,trehalose, sucrose, polyvinylpyrrolidone, lactose, inositol, sorbitol,dimethylsulfoxide, glycerol, albumin, calcium lactobionate, and othersknown to those of ordinary skill in the art.

A solubility-enhancing agent or solubility enhancer can be added to theformulation of the invention. A solubility-enhancing agent is acompound, or compounds, that enhance(s) the solubility of thecorticosteroid when in an aqueous liquid carrier. When anothersolubility enhancing agent is present, the ratio of SAE-CD tocorticosteroid can be changed, thereby reducing the amount of SAE-CDrequired to dissolve the corticosteroid. Suitable solubility enhancingagents include one or more cyclodextrins, cyclodextrin derivatives,SAE-CD, organic solvents, detergents, soaps, surfactant and otherorganic compounds typically used in parenteral formulations to enhancethe solubility of a particular agent. Exemplary solubility enhancers aredisclosed in U.S. Pat. No. 6,451,339; however, other surfactants used inthe pharmaceutical industry can be used in the formulation of theinvention. Some suitable cyclodextrin include underivatizedcyclodextrins and cyclodextrin derivatives, such as SAE-CD, SAE-CDderivatives, hydroxyalkyl ether cyclodextrin and derivatives, alkylether cyclodextrin and derivatives, sulfated cyclodextrin andderivatives, hydroxypropyl-β-cyclodextrin, 2-HP-β-CD,methyl-β-cyclodextrin, carboxyalkyl thioether derivatives, succinylcyclodextrin and derivatives, and other cyclodextrin suitable forpharmaceutical use. SAE-CD cyclodextrins are particularly advantageous.

Suitable surfactants include phospholipids, among other compounds, whichinclude for example phosphocholines or phosphatidylcholines, in whichthe phosphate group is additionally esterified with choline, furthermorephosphatidyl ethanolamines, phosphatidyl inositols, lecithins. Otherionic surfactants which can serve as solubility-enhancing agents are,for example, sodium lauryl sulfate, sodium cetylstearyl sulfate, sodium(or calcium or potassium) docusate, medium and long chain fatty acids.

SAE-CD can serve as a taste-masking agent by complexation withpoor-tasting molecule. For example, SAE-CD can complex with a bitter orsour tasting active agent in a composition of the invention to reducethe bitterness or sourness of the agent as compared to the uncomplexedactive agent. Accordingly, “improved taste” or “taste-masking” is takento mean a reduction in the bitterness or sourness of a composition oractive agent. Active agents can differ in the native bitterness orsourness. For example, olopatadine is known to have reduced bitternessas compared to azelastine. The invention includes taste-maskedembodiments, wherein the SAE-CD is complexed with an active agent havingreduced bitterness or reduced sourness as compared to another activeagent.

In some embodiments, the methods, systems, devices, and compositions ofthe invention are associated with improved taste of a therapeutic agentas compared to the therapeutic agent alone or in existing formulations.In some embodiments, the improved taste is associated withadministration of an antihistamine. In some embodiments, the improvedtaste is associated with administration of azelastine. The effectivenessof SAE-CD at masking the taste of a drug can be determined, for example,according to Example 31, which details the procedure used to conduct anelectronic tongue study on a composition comprising SBE-β-CD andazelastine.

If desired, the composition further comprises an aqueous liquid carrierother than water. Suitable organic solvents that can be used in theformulation include, for example, ethanol, glycerin, poly(ethyleneglycol), propylene glycol, poloxamer, aqueous forms thereof, othersknown to those of ordinary skill in the art and combinations thereof.

It should be understood that compounds used in the art of pharmaceuticalformulations generally serve a variety of functions or purposes. Thus,if a compound named herein is mentioned only once or is used to definemore than one term herein, its purpose or function should not beconstrued as being limited solely to that named purpose(s) orfunction(s).

A composition can be purged with an inert gas prior to storage to removesubstantially all of the oxygen contained in the formulation. Ingeneral, the formulation or composition of the invention has ashelf-life of at least 6 months depending upon the intended use.

If needed, the SAE-CD-containing formulation can be prepared as a clearaqueous solution that can be sterile filtered through a filter having apore size of 0.45 μm or less and that is stable and preserved under avariety of storage conditions. The invention thus provides afiltration-sterilized liquid formulation comprising a solution of theinvention and a method of sterilizing a solution of the invention bysterile filtration through a filter. Sterile filtration can be donewithout substantial mass loss of solubilized corticosteroid, meaningless than 5% mass loss.

The formulation can be prepared at a temperature at or above 5° C., ator above 25° C., at or above 35° C., at or above 45° C. or at or above50° C. Specific embodiments of the methods of preparing a liquidformulation include those wherein: 1) the method further comprisessterile filtering the formulation through a filtration medium having apore size of 0.1 microns or larger; 2) the liquid formulation issterilized by irradiation or autoclaving; and/or 3) the nebulizationsolution is purged with nitrogen or argon or other inertpharmaceutically acceptable gas prior to storage such that a substantialportion of the oxygen dissolved in, and/or in surface contact with thesolution is removed.

An active agent contained within the present formulation can be presentas its pharmaceutically acceptable salt. As used herein,“pharmaceutically acceptable salt” refers to derivatives of thedisclosed compounds wherein the active agent is modified by reacting itwith an acid or base as needed to form an ionically bound pair. Examplesof pharmaceutically acceptable salts include conventional non-toxicsalts or the quaternary ammonium salts of the parent compound formed,for example, from non-toxic inorganic or organic acids. Suitablenon-toxic salts include those derived from inorganic acids such ashydrochloric, hydrobromic, sulfuric, sulfonic, sulfamic, phosphoric,nitric and others known to those of ordinary skill in the art. The saltsprepared from organic acids such as amino acids, acetic, propionic,succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic,pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic,salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic,methanesulfonic, ethane disulfonic, oxalic, isethionic, and others knownto those of ordinary skill in the art. The pharmaceutically acceptablesalts of the present invention can be synthesized from the parent activeagent which contains a basic or acidic moiety by conventional chemicalmethods. Lists of other suitable salts are found in Remington'sPharmaceutical Sciences, 17^(th). ed., Mack Publishing Company, Easton,Pa., 2005, the relevant disclosure of which is hereby incorporated byreference.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used herein, the term “patient” or “subject” are taken to mean humansand non-humans, such as mammals, for example, cats, dogs, mice, guineapigs, horses, bovine cows, and sheep.

The utility and therapeutic efficacy of a nasal aqueous liquidcomposition according to the invention for the treatment of seasonalallergic rhinitis (SAR)/conjunctivitis (SARC) was demonstrated in aclinical trial conducted according to Example 33.

The time to target or peak therapeutic effect is the period of timeafter administration of a dose that it takes for the active agent toachieve the target or peak therapeutic effect, respectively, in asubject. The onset of a target or desired therapeutic effect is thepoint in time that the beginning of the target or desired therapeuticeffect is first observed in the subject after administration of acomposition.

In some embodiments, the compositions, methods, and systems of theinvention relieve non-nasal symptoms sooner and to a greater degree thanan aqueous suspension-based formulation comprising the same unit dose ofcorticosteroid and administered under substantially the same conditionsbut excluding SAE-CD. In some embodiments, the compositions and systemsprovide more rapid relief of nasal symptoms than the aqueous suspensionbased formulation. The compositions and systems of the invention alsoprovide simplified manufacture, improved administered-dose uniformity,and improved taste-masking and odor-masking as compared to the aqueoussuspension-based formulation. In some embodiments, the compositions,methods, and systems of the invention provide an enhanced and/or morerapid onset of a target or desired therapeutic effect and/or a morerapid time to target, desired or peak therapeutic effect as compared tothe aqueous suspension-based compositions, methods, or systems excludingSAE-CD.

A therapeutic effect will be observed following administration of acomposition. The onset of a target or desired therapeutic effect is thepoint in time that the beginning of the target or desired therapeuticeffect is first observed in the subject after administration of acomposition. In some embodiments, the onset of a target or desiredtherapeutic effect generally occurs within 0.1 min to 120 min, 1 min to90 min, 1 min to 60 min, 1 min to 30 min, 1 min to 20 min, 1 min to 15min, or 1 min to 10 min after nasal or ophthalmic administration of thecomposition.

In some embodiments, the time to a target or peak therapeutic effect canoccur from minutes to hours after administration. In some embodiments,the time to target can occur from 8 to 10 hours, within 1 to 2 days, orwithin 1 to 2 weeks after nasal or ophthalmic administration of thecomposition, said administration being conducted according to a dosingregimen as detailed herein.

In some embodiments, the methods, systems, devices, and compositions ofthe invention comprise a combination of corticosteroid and azelastinewith SAE-CD in a solution that is useful for treating nasal, non-nasal,and ocular symptoms. In some embodiments, the symptoms are allergicsymptoms resulting from exposure of a subject to an airborne allergen.

A clinical study according to Example 34 was conducted to demonstratethe therapeutic efficacy of a nasal composition comprising budesonide,azelastine hydrochloride, CAPTISOL and buffer as compared to thesequential administration of RHINOCORT AQUA (RA) and ASTELIN (AST).

In some embodiments, the nasal compositions, systems, and methods of theinvention comprising a corticosteroid, SAE-CD and an antihistamineprovides a therapeutic effect (clinical benefit) that approximates or isenhanced over the therapeutic effect provided by the separate andsequential nasal administration of: a) an aqueous suspension compositioncomprising the same unit dose of corticosteroid; and b) an aqueouscomposition comprising the same unit dose of antihistamine. In someembodiments, the therapeutic effect is relief of nasal, non-nasal andocular allergic symptoms. In some embodiments, the nasal composition,system and method of the invention provide an improved quality of lifein subjects suffering from an allergic disorder, such as SAR and/orSARC.

The compositions, methods, and systems of the invention can provide anenhanced therapeutic effect as compared to a suspension-based aqueousformulation of corticosteroid. The enhanced therapeutic effect canbe: 1) enhanced or better relief of non-nasal symptoms (especiallyocular symptoms); 2) a more rapid onset of therapeutic effect; 3) a morerapid time to peak or target therapeutic effect; 4) more rapid relief ofnasal symptoms; 5) enhanced or better relief of nasal symptoms; 6) morerapid relief of non-nasal symptoms; 7) enhanced quality of life,especially emotional status or practical problems; and/or 8) reducedcorticosteroid-related side effects, such as epistaxis, dryness, orburning.

In some embodiments, the corticosteroid solutions of the inventionprovide more rapid relief of a symptom or disorder, such as an allergicsymptom or disorder, when compared with a corticosteroid suspension atthe same unit dose and under substantially similar conditions. In someembodiments, the corticosteroid solutions of the invention provide arate of relief that is about 25%, about 35%, about 45%, about 50%, about60%, or about 75% more rapid when compared with a corticosteroidsuspension at the same unit dose and under substantially similarconditions. In some embodiments, the corticosteroid solutions of theinvention provide a rate of relief that is about 1.2-fold greater, about1.5-fold greater, about 2-fold greater, about 2.5-fold greater, about3-fold greater, about 4-fold greater, or about 5-fold greater than acorticosteroid suspension at the same unit dose and under substantiallysimilar conditions.

An in vivo study according to Example 41 was conducted in rabbits tocompare the ability of budesonide to provide an anti-inflammatorytherapeutic effect or other clinical benefit.

In some embodiments, the corticosteroid solutions of the methods,systems, devices, and compositions of the present inventions areadministered ophthalmically for the treatment of ocular symptoms. Insome embodiments, the corticosteroid solutions of the inventions areadministered for the treatment of nasal symptoms when administeredophthalmically.

In some embodiments, the corticosteroid solutions of the inventionprovide more rapid relief in the treatment of ocular and nasal symptomscompared to other corticosteroid solutions or suspensions at the sameunit dose when administered ophthalmically. In some embodiments, theocular symptom is inflammation. In some embodiments, the corticosteroidsolutions of the invention allow for a more rapid reduction in ocularinflammation compared to other corticosteroid solutions or suspensionswhen administered ophthalmically. In some embodiments, thecorticosteroid solutions of the invention provide more rapid relief oftotal ocular symptoms based on a Total Ocular Symptom Score (TOSS) usinga visual analogue scale (TOSS-VAS) of subjects or a five point scale(0-4) of subjects with allergic conjunctivitis exposed to controlledragweed pollen using an EEC model compared with other corticosteroidsolutions or suspensions at the same unit dose when administeredophthalmically. In some embodiments, the corticosteroid solutions of theinvention provide a greater relief of TNSS compared with othercorticosteroid solutions or suspensions at the same unit dose whenadministered ophthalmically. In some embodiments, the corticosteroidsolutions of the invention provide more rapid onset of action in thetreatment of allergic rhinitis compared with other corticosteroidsolutions or suspensions at the same unit dose when administeredophthalmically. In some embodiments, the corticosteroid solutions of theinvention provide a reduced dose of corticosteroid to elicit anequivalent or greater therapeutic effect as provided by othercorticosteroid solutions or suspensions at higher unit doses whenadministered ophthalmically. In some embodiments, the corticosteroidsolutions of the invention provide improved dose uniformity amongseparate unit doses compared to unit doses provided by othercorticosteroid solutions or suspensions when administeredophthalmically. In some embodiments, the corticosteroid solutions of theinvention are more easily manufactured than other corticosteroidsolutions or suspensions for ophthalmic administration. In someembodiments the corticosteroid solution for ophthalmic administrationcomprises one or more additional therapeutic agents, such as anantihistamine. In some embodiments, the corticosteroid solutionadditionally comprises azelastine.

When comparing the performance of a liquid composition of the inventionto the performance of a suspension-based composition, it is assumed thatadministration of the two compositions will be conducted using the sameadministration device, the same unit dose or total dose, substantiallythe same dosing regimen, and/or substantially the same administrationprocedure.

All the various embodiments or options described herein can be combinedin any and all variations. In some embodiments, the subject inventioncomprises combinations of SAE-CD, corticosteroid and a pharmaceuticallyacceptable aqueous liquid carrier, which specifically exclude one ormore (but not all) of the SAE-CDs and one or more (but not all) of thecorticosteroids described herein. In additional embodiments, the subjectinvention may comprise combinations of SAE-CDs, corticosteroids,antihistamines and an aqueous liquid carrier, said combinationsspecifically excluding one or more of the antihistamines describedherein.

The following examples should not be considered exhaustive, but merelyillustrative of only a few of the many embodiments contemplated by thepresent invention.

Example 1

Exemplary formulations according to the invention were made according tothe following general procedures.

Method A

Cyclodextrin is dissolved in water (or buffer) to form a solutioncontaining a known concentration of cyclodextrin. This solution is mixedwith an active agent in solid, suspension, gel, liquid, paste, powder orother form while mixing, optionally while heating to form a solution.

Method B

A known amount of substantially dry cyclodextrin is mixed with a knownamount of substantially dry active agent. A liquid is added to themixture to form a suspension, gel, solution, syrup or paste whilemixing, optionally while heating and optionally in the presence of oneor more other excipients, to form a solution.

Method C

A known amount of substantially dry cyclodextrin is added to asuspension, gel, solution, syrup or paste comprising a known amount ofactive agent while mixing, optionally while heating and optionally inthe presence of one or more other excipients, to form a solution.

The methods of this example can be modified by the inclusion of awetting agent in the composition in order to facilitate dissolution andsubsequent inclusion complexation of the corticosteroid. A surfactant,soap, detergent or emulsifying agent can be used as a wetting agent.

Method D

To a solution comprising a known concentration or amount of SAE-CD,aqueous liquid carrier, and optionally one or more other excipients, isadded a molar excess of the corticosteroid based upon the molar ratio ofSAE-CD to corticosteroid at the point of saturated solubility of thecorticosteroid, in the presence of the SAE-CD, as determined herein. Forexample, corticosteroid would be added at a 5%, 10%, 15%, 20%, 25%, 30%or greater molar excess. The components are mixed until equilibration,the point at which there is only a minor change in the concentration ofbudesonide over a one-hour period of time. Then, the excesscorticosteroid is removed leaving behind the target solution of theinvention.

The budesonide is added to the SAE-CD-containing solution as either asolid or suspension in an aqueous liquid carrier, which can be water,buffer, aqueous alcohol, aqueous organic solvent or a combinationthereof. The alcohol and organic solvent are of a pharmaceuticallyacceptable grade, such as ethanol, propylene glycol, and others asdescribed herein.

Method E

The SAE-CD and corticosteroid are triturated to form a mixture. Then, anaqueous liquid carrier is added to the mixture form the target solutionof the invention.

The trituration can be conducted dry or in the presence of moisture,water, buffer, alcohol, surfactant, organic solvent, glycerin,poly(ethylene glycol), poloxamer, or a combination thereof.

Method F

Any of the methods herein are conducted in the presence of heat, e.g. ata temperature of least 40° C.

Method G

Any of the methods herein are conducted with cooling, e.g. at atemperature of less than 20° C. or less than 10° C. or less than 5° C.

Method H

Any of the methods herein are conducted in the presence of high shearmixing such as with a sonicator, narrow gauge syringe(s),mixer/homogenizer (POLYTRON from KINEMATICA, Europe; FLUKO, Shanghai,China; ULTIMAGRAL from GEA Niro, Inc., Columbia, Md.), rotor-statormixer, or saw tooth mixer.

Method I

Any of the methods herein are conducted under reduced pressure.

Method J

The aqueous corticosteroid solution can be prepared by diluting aconcentrated corticosteroid solution with water, buffer, or otheraqueous liquid carrier.

Example 2

The MMD of nebulized solutions containing SBE7-β-CD and budesonide wasdetermined as follows.

Placebo solutions of three different cyclodextrins were prepared atdifferent concentrations. Two mL of the solutions were added to the cupof a Pari LC Plus nebulizer supplied with air from a Pari Proneb Ultracompressor. The particle size of the emitted droplets was determinedusing a Malvern Mastersizer S laser light scattering instrument.

Example 3

The content of corticosteroid in aqueous solutions containing SAE-CD wasdetermined by HPLC chromatography of aliquots periodically drawn fromthe liquid in storage.

Citrate-phosphate (McIlvaines) buffer solutions at a pH of 4, 5, 6, 7,or 8 were prepared by mixing various portions of 0.01M citric acid with0.02 M Na₂HPO₄. These stock solutions contained 5% w/w CAPTISOL.Approximately 250 μg/mL of budesonide was dissolved in each buffersolution. Aliquots of the solutions were stored at 40° C., 50° C. and60° C. Control samples were stored at 5° C. but are not reported here.HPLC analysis of the samples was performed initially and after 1, 2, and3 months storage.

The HPLC conditions included:

Instrument: PE Series 200 Column: Phenomenex Luna C18(2) 4.6 × 150 mm3um Mobile Phase: 58% Phosphate Buffer pH 3.4/39.5% ACN/ 2.5% MeOHMobile Phase Program: 100% A (isocratic) Wavelength 240 Flow Rate: 0.6mL/min Standard Range: Seven standards - 1 to 500 μg/mL

Example 4

The viscosity of aqueous solutions containing SAE-CD was measured usinga cone and plate viscometer.

A Brookfield Programmable DV-III+ Rheometer, CPE-40 cone and CPE 40Yplate (Brookfield Engineering Laboratories, Middleboro, Mass.) was usedto make measurements on 0.5 mL samples at 1, 2, 3, 5 and 10 rpm. Sampleswere sheared for approximately 5 revolutions prior to each measurement.This allowed accurate rheological characterization of the samples. Thetemperature of all samples was equilibrated to 25+/−1 degree centigradeusing a double wall viscometer cone supplied with water from anelectronically controlled thermostatic circulating water bath (Model,8001, Fisher Scientific, Pittsburgh, Pa.). The viscometer was calibratedusing 5 and 50 centipoise using silicon oil calibration standards.Viscosity measurements were made at 5 or more rotation speeds to lookfor sheer thinning behavior (viscosities that decrease as the rate ofsheer increases). Higher rotation speeds result in increased rates ofshear.

Example 5

Nebulizer output rate as a function of SAE-CD concentration was measuredaccording to the following general procedure.

Nebulizer Output was tested using Pari LC Plus Nebulizer with a PariProNeb Ultra Air Compressor (Minimum Nebulizer Volume=2 mL, MaximumNebulizer Volume=8 mL) for solutions containing 43%, 21.5%, 10.75% and5.15% w/w SBE7-β-CD. Percentage of sample emitted was estimatedgravimetrically. The nebulizer cup was weighed before and afternebulization was complete. Nebulization Time was defined as the durationof time when nebulizer run was started until the time of first sputter.Nebulizer Output Rate was calculated by dividing % Emitted withNebulization Time.

Example 6

Preparation of a solution containing budesonide.

A buffer solution containing 3 mM Citrate Buffer and 82 mM NaCl at pH4.45 is prepared. ˜12.5 grams of CAPTISOL was placed into a 250 mLvolumetric flask. ˜62.5 mg of budesonide was placed into the same flask.Flask was made to volume with the 3 mM citrate buffer/82 mM NaClsolution. The flask was well-mixed on a vortexer for 10 minutes andsonicated for 10 minutes. The flask was stirred over weekend withmagnetic stirrer. Stirring was stopped after ˜62 hours and flask wasrevortexed and resonicated again for 10 minutes each. The solution wasfiltered through a 0.22 μm Durapore Millex-GV Millipore syringe filterunit. The first few drops were discarded before filter rest of solutioninto an amber glass jar with a Teflon-lined screw cap. Sampleconcentration was ˜237 μg/mL.

Example 7

Preparation of a solution containing budesonide.

Approximately 5 grams of CAPTISOL was placed into a 100 mL volumetricflask. ˜26.3 mg of budesonide was placed into the same flask. The flaskwas made to volume with the 3 mM citrate buffer/82 mM NaCl solution. Themixture was well-mixed on a vortexer for 10 minutes and sonicated for 10minutes. The mixture was stirred overnight with a magnetic stirrer.Stirring was stopped after ˜16 hours and flask was revortexed andresonicated again for 10 minutes each. The solution was filtered through0.22 μm Durapore Millex-GV Millipore syringe filter unit. The first 5drops were discarded before filter rest of solution into an amber glassjar with a Teflon-lined screw cap. Sample was analyzed to be 233 μgbudesonide/mL.

Example 8

Preparation of a solution containing budesonide.

The procedure of Example 7 was followed except that 12.5 g of CAPTISOL,62.5 mg of budesonide and about 250 mL of buffer were used. Sufficientdisodium EDTA was added to prepare a solution having an EDTAconcentration of about 0.01 or 0.05% wt/v EDTA.

Example 9

Preparation of a solution containing SAE-CD and budesonide as preparedfrom a PULMICORT RESPULES suspension.

Method A

To the contents of one or more containers of the PULMICORT RESPULES(nominally 2 mL of the suspension), about 50 mg (corrected for watercontent) of CAPTISOL was added per mL of Respule and mixed or shakenwell for several minutes. After standing from about 30 minutes toseveral hours, the solution was used as is for in vitrocharacterization. In addition to budesonide and water, the PULMICORTRESPULE (suspension) also contains the following inactive ingredientsper the label: citric acid, sodium citrate, sodium chloride, disodiumEDTA and polysorbate 80.

Method B

Weigh approximately 200 mg amounts of CAPTISOL (corrected for watercontent) into 2-dram amber vials. Into each vial containing the weighedamount of CAPTISOL empty the contents of two PULMICORT RESPULEScontainers (0.5 mg/2 mL, Lot # 308016 February 5) by gently squeezingthe deformable plastic container to the last possible drop. The Respuleswere previously swirled to re-suspend the budesonide particles. Thevials are screw capped, mixed vigorously by vortex and then foilwrapped. The material can be kept refrigerated until use.

The liquid composition prepared according to any of these methods can beused in any known administration device. By converting the suspension toa liquid, an improvement in delivery of budesonide (a corticosteroid) isobserved.

Example 10

Other solutions according to the invention can be prepared as detailedbelow.

Mg per mL Mg per mL (as prepared) (per target) Component Concentrate AConcentrate B Final Solution Budesonide EP 1 ~1.6 (sat'd) 0.250 CAPTISOL200 200 50 Sodium Citrate tribasic 0 0 0.44 dihydrate Citric Acid 0 00.32 Sodium Chloride 0 0 4.8 Disodium EDTA 0 0 0-0.5 Polysorbate 80 0 00-1   (TWEEN 80) Water Qs Qs QS with buffer containing CAPTISOL orbudesonide

-   -   Dilute Concentrate A at a ratio of 1 to 4 with pH 4.5 salinated        citrate buffer (4 mM containing 109 mM sodium chloride) to        contain 5% w/v CAPTISOL on an anhydrous basis. Filter the        diluted concentrate through a 0.22 μm Millipore Durapore        Millex-GV syringe filter unit. Assay the filtered solution by        HPLC then add supplemental budesonide as needed to give a        solution final concentration of about 250 μg/mL (±<5%).    -   Dilute Concentrate B at a ratio of 1 to 4 with pH 4.5 salinated        citrate buffer (4 mM containing 109 mM sodium chloride) to        contain 5% w/v CAPTISOL on an anhydrous basis. Filter the        diluted concentrate through a 0.22 μm Millipore Durapore        Millex-GV syringe filter unit. Assay the filtered solution by        HPLC then dilute further with pH 4.5 salinated citrate buffer (3        mM containing 82 mM sodium chloride containing 5% w/v CAPTISOL)        as required to give a final solution concentration of about 250        μg/mL (±<5%). This technique takes advantage of the excess solid        budesonide used to saturate the solution.

Example 11

Clarity of solutions was determined by visual inspection orinstrumentally. A clear solution is at least clear by visual inspectionwith the unaided eye.

Example 12

The following method was used to determine the performance ofnebulization compositions emitted from a nebulizer.

Two mL of the test CD solution or Pulmicort suspension was accuratelypipetted by volumetric pipettes into a clean nebulizer cup prior tostarting each experiment. The test nebulizer was assembled and chargedwith the test solution or suspension according to the manufacturerinstructions. The end of the mouthpiece was placed at a height ofapproximately 18 cm from the platform of the MALVERN MASTERSIZER to themiddle point of tip of the nebulizer mouthpiece. A vacuum source waspositioned opposite the mouthpiece approximately 6 cm away to scavengeaerosol after sizing. The distance between the mouthpiece and thedetector was approximately 8 cm. The center of the mouthpiece was levelwith the laser beam (or adjusted as appropriate, depending on theindividual design of each nebulizer). The laser passed through thecenter of the emitted cloud when the nebulizer was running. Measurementswere manually started 15 seconds into nebulization. Data collectionstarted when beam obscuration reached 10% and was averaged over 15,000sweeps (30 seconds). Scattered light intensity data on the detectorrings was modeled using the “Standard-Wet” model. Channels 1 and 2 werekilled due to low relative humidity during measurement to prevent beamsteering. The volume diameter of droplets defining 10, 50 (volumemedian), and 90% of the cumulative volume undersize was determined.(Dv10 is the size below which 10% of the volume of material exists, Dv50is the size below which 50% of the volume of material exists and Dv90 isthe size below which 90% of the volume of material exists.

The procedure above can be practiced with slight modification on aMALVERN SPRAYTEC to determine the particle size of droplets emitted by anebulizer.

Example 13

Solutions of budesonide with and without SBE7-β-CD were prepared at twodifferent pHs (4 and 6) and stored at 2 different temperatures (60° C.and 80° C.). Citrate buffers (50 mM) at each pH value were prepared bymixing differing portions of 50 mM citric acid and 50 mM sodium citrate(tribasic, dihydrate) solutions. To achieve a concentration ofbudesonide in the buffers without SBE7-β-CD sufficient for accuratemeasurement, the budesonide was dissolved first in 100% ethyl alcohol.An aliquot of the ethanol/budesonide solution was then added drop-wisewith stirring to each buffer solution. The theoretical budesonideconcentration was 100 μg/mL with a final ethanolic content of 5% in eachbuffer. All solution preps and procedures involving budesonide were donein a darkened room under red light. After shaking solutions for 24hours, both buffer solutions were filtered through Millipore Millex-GV0.22 μm syringe filters to remove any solid that had precipitated (nosignificant amounts observed) from the solutions. The final budesonideconcentration was about 50 μg/mL. Both the pH 4 and 6 solutions weresplit in two, and solid SBE7-β-CD was added to one of the portions tocreate solutions with and without 1% w/v SBE7-β-CD at each pH. Eachsolution was aliquoted into individual amber vials. They were thenplaced in ovens at 60° C. and 80° C. Sample vials were removed from theovens and analyzed by HPLC at 0, 96, 164, and 288 hours. The HPLC assayconditions are summarized below.

Chromatographic Conditions

(Adapted from Hou, S., Hindle, M., and Byron, P. R. A.Stability-Indicating HPLC Assay Method for Budesonide. Journal ofPharmaceutical and Biomedical Analysis, 2001; 24: 371-380.)

Instrument: PE Series 200 Column: Phenomenex Luna C18(2) 4.6 × 150 mm3um Mobile Phase: 58% Phosphate Buffer pH 3.4/39.5% ACN/ 2.5% MeOHMobile Phase Program: 100% A (isocratic) Wavelength 240 nm Flow Rate:0.6 mL/min Standard Range: Seven standards - 1 to 500 μg/mL

Example 14

Preparation of solution comprising SAE-CD (10% wt.), budesonide (500μg/mL), and azelastine hydrochloride (0.2% wt.).

CAPTISOL (2.37 g) was weight into an amber vial. Azelastinehydrochloride (43.8 mg) was weighed into the same vial. PULMICORTNEBUAMPs (10) were mixed vigorously for 1 min. The contents of eachNEBUAMP were dispensed into the amber vial containing CAPTISOL andazelastine and mixed by vortexing, shaking, sonication and overnightmixing on a roller mixer to permit equilibration. The resulting solutionwas clear.

Example 15

The temperature stability of the composition of Example 14 wasdetermined as follows.

The solution of Example 14 was divided into vials and grouped and storedat 25° C., 40° C., or 60° C. A control sample was stored at 5° C. Thesamples were stored for 10 days and two vials were removed for analysisat 0, 3, and 10 days. Assay samples were prepared by drawing one aliquotfrom each vial, diluting 200 μL with 800 μL of mobile phase (see below),and assaying the samples by HPLC according to the European Pharmacopeia,Monograph 1633E for “azelastine hydrochloride” (version 5.0 correctedJanuary 2005).

Example 16

The pH and temperature stability of an aqueous liquid compositioncomprising SAE-CD, azelastine, and buffer were determined as follows.

Aqueous solutions comprising azelastine HCl (0.5 mg/mL) with and withoutCAPTISOL (1.75% wt.) were prepared. Stock citrate solutions (sodiumcitrate (3 mM) and citric acid solution (3 mM); 500 mL each) wereprepared. The citrate solutions were combined and titrated to preparestock buffered solutions (at least 150 mL each) having a pH of 4, 5, or6. A stock solution of azelastine hydrochloride (5 mg/mL) in water wasprepared. Assay solutions comprising CAPTISOL, azelastine and bufferwere prepared by mixing CAPTISOL (1.4 g) and stock solution ofazelastine (7.5 mL) in stock buffered solution (QS to final volume of 75mL for each different pH). Assay solutions comprising azelastine andbuffer were prepared by mixing stock solution of azelastine (7.5 mL) andstock buffered solution (67.5 mL, or QS to final volume of 75 mL). Sixassay solutions were prepared as follows: 1) pH 4-azelastine only; 2) pH4-azelastine+CAPTISOL; 3) pH 5-azelastine only; 4) pH5-azelastine+CAPTISOL; 5) pH 6-azelastine only; 6) pH6-azelastine+CAPTISOL. Portions of each assay solution were stored at25° C., 40° C., and 60° C. for a period of sixteen weeks. Aliquots ofthe assay solutions were taken at 0, 1, 2, 4, 8, 12, and 16 weeks. Thealiquots were assayed by HPLC as described herein. Control samples foreach assay solution were stored at 5° C. to provide reference points.

Example 17

Exemplary compositions of the invention packaged in various multi-dosevolume metered dose pump spray devices are made to include the followingingredients in the amounts specified according to the procedure below.

100 μL 137 μL 50 μL Spray 70 μL Spray Spray Spray Ingredient Function(mg/mL) (mg/mL) (mg/mL) (mg/mL) Budesonide Active Substance 0.64 0.460.32 0.234 CAPTISOL Solubilizer/Stabilizer 96 68 48 36 Disodium edetate,Antioxidant 0.1 0.1 0.1 0.1 Sodium chloride, Tonicity modifier 0 27 4556 Citric acid, Buffer 0.3 0.3 0.3 0.3 Sodium citrate Buffer 0.5 0.5 0.50.5 dihydrate Polysorbate 80 Surfactant optional optional optionaloptional 0.05 mg/mL Potassium Sorbate Antimicrobial optional optionaloptional optional 1 mg/mL Sterile water for Solvent q.s. to 1.0 mL q.s.to 1.0 mL q.s. to 1.0 mL q.s. to 1.0 mL injection, Budesonide ActiveSubstance 0.64 0.46 0.32 0.234 Azelastine HCl Active Substance 2.74 1.961.37 1.00 CAPTISOL Solubilizer/Stabilizer 128 91 64 48 Disodium edetate,Antioxidant 0.1 0.1 0.1 0.1 Sodium chloride, Tonicity modifier 0 27 4556 Citric acid, Buffer 0.3 0.3 0.3 0.3 Sodium citrate Buffer 0.5 0.5 0.50.5 dihydrate Polysorbate 80 Surfactant optional optional optionaloptional 0.05 mg/mL Potassium Sorbate Antimicrobial optional optionaloptional optional 1 mg/mL Sterile water for Solvent q.s. to 1.0 mL q.s.to 1.0 mL q.s. to 1.0 mL q.s. to 1.0 mL injection,

Compositions comprising the specified concentrations of ingredients areprepared and packaged into multi-dose metered volume pump spray devices.The compositions optionally comprise potassium sorbate at aconcentration of about 1 mg/mL and/or polysorbate 80 at a concentrationof about 0.005%. Each package contains approximately 120 doses plus anoverfill of the composition. Suitable packages for the specified sprayvolumes include:

-   -   1. 50 μL Spray volume: 9 mL of composition in a 10 mL bottle;        for example 20242 02 001 diagnostic 6/8 amber glass type 1 400        20 neck finish bottle fitted with Nasal Spray Pump having a 50        μL dose volume, 20/400 screw closure, and 42.0 mm dip tube        length;    -   2. 70 μL Spray volume: 13 mL of composition in a 15 mL amber        glass bottle;    -   3. 100 μL Spray volume: 17 mL of composition in a 20 mL amber        glass vial;    -   4. 137 μL Spray volume: 24 mL of composition in a 24 mL amber        glass vial.

Example 18

Comparative evaluation of various forms of SAE-CD in the solubilizationof corticosteroid derivatives.

The solubility of beclomethasone dipropionate (BDP), beclomethasone17-monopropionate (B17P), beclomethasone 21-monopropionate (B21P) andbeclomethasone (unesterifed) in solutions containing CAPTISOL andvarious SBE_(n)γ-CD was evaluated. BDP, B17P and B21P were obtained fromHovione. Beclomethasone was obtained from Spectrum Chemicals. CAPTISOL,SBE(3.4) γ-CD, SBE(5.23) γ-CD and SBE(6.1) γ-CD were provided by CyDex,Inc. (Lenexa, Kans.). γ-CD was obtained from Wacker Chemical Co.SBE(5.24) γ-CD and SBE(7.5) γ-CD were provided by the University ofKansas.

A 0.04M solution of each selected CD was prepared. Each form ofbeclomethasone required 2 mL of CD solution, therefore the 0.04Msolutions were prepared in 20 or 25 mL volumetric flasks in duplicate(N=2). The following table indicates the amount of each CD used afteraccounting for the content of water in each CD.

CD MW (g/mole) mg of CD (volume) SBE(6.7) β-CD 2194.6 2297.0 (25 mL)γ-CD 1297 1433.0 (25 mL) SBE(3.4) γ-CD 1834.9 1891.6 (25 mL) SBE(5.24)γ-CD 2119.5 1745.7 (20 mL) SBE(6.1) γ-CD 2261.9 1866.8 (20 mL) SBE(7.5)γ-CD 2483.3 2560.0 (25 mL)

Beclomethasone forms were weighed in amounts in excess of theanticipated solubilities directly into 2-dram Teflon-lined screw-cappedvials. These amounts typically provided approximately 6 mg/mL of solids.Each vial then received 2 mL of the appropriate CD solution. The vialswere vortexed and sonicated for about 10 minutes to aid in wetting thesolids with the fluid. The vials were then wrapped in aluminum foil toprotect from light and placed on a lab quake for equilibration. Thevials were visually inspected periodically to assure that the solidswere adequately being wetted and in contact with the fluid. The timepoints for sampling were at 24 hrs for all samples and 72 hours for BDPonly.

Solutions of SBE(6.1) γ-CD were prepared at 0.04, 0.08, and 0.1M andsolutions of SBE (5.23) γ-CD were prepared at only 0.04 and 0.08M.Beclomethasone dipropionate was weighed in amounts in excess of theanticipated solubilities directly into 2-dram teflon-lined screw-cappedvials. These amounts typically provided approximately 2 mg/mL of solids.Each vial then received 2 mL of the appropriate CD solution (N=1). Thevials were vortexed and sonicated for about 10 minutes to aid in wettingthe solids with the fluid. The vials were then wrapped in aluminum foilto protect from light and placed on a lab quake for a five-dayequilibration.

Solutions of γ-CD were prepared at 0.01 and 0.02M. Beclomethasonedipropionate was weighed in amounts in excess of the anticipatedsolubilities directly into 2-dram teflon-lined screw-capped vials. Theseamounts typically provided approximately 2 mg/mL of solids. Each vialthen received 2 mLs of the γ-CD solution (N=2). A solution was alsoprepared to measure the intrinsic solubility of BDP using HPLC gradewater in place of the CD. The samples were wrapped in foil and placed ona lab quake for five days.

At the end of the equilibration time for each stage, the vials werecentrifuged and 1 mL of the supernatant removed. The removed supernatantwas then filtered using the Durapore PVDF 0.22 μm syringe filter(discarded first few drops), and diluted with the mobile phase to anappropriate concentration within the standard curve. The samples werethen analyzed by HPLC to determine concentration of solubilizedcorticosteroid. The data are detailed below.

Beclomethasone Beclomethasone Beclomethasone 17-mono- 21-mono-Beclomethasone dipropionate propionate propionate (unesterified) CD(μg/mL) (μg/mL) (μg/mL) (μg/mL) SBE_(3.4) 0.04M → 336.8 0.04M → 10621.60.04M → 172.6 0.04M → 11360.2 γ-CD SBE_(5.24) 0.04M → 267.0 0.04M →9500.8 0.04M → 139.8 0.04M → 10949.9 γ-CD SBE_(6.1) 0.04M → 243.8 0.04M→ 11666.9 0.04M → 153.8 0.04M → 11007.0 γ-CD SBE_(7.5) 00.04M → 168.5 0.04M → 8539.1 0.04M → 122.4 0.04M → 9635.2 γ-CD SBE_(6.7) 0.04M → 60.4 0.04M → 6799.6 0.04M → 50.6 0.04M → 6927.0 β-CD γ-CD 0.04M → 105.8 0.04M→ 136.9 0.04M → 9.4 0.04M → 114.8

The survey study shows that in the presence of SBE(3.4) γ-CD (0.04M),all of the forms of beclomethasone were at or near their highestsolubilities. B17P, the active metabolite of BDP, has the highestsolubility of the esterified beclomethasone forms in any of thederivatized CDs. The results indicate that SBE-γ-CD complexes withbeclomethasone dipropionate better than CAPTISOL or γ-CD alone. Of theSAE-CD derivatives evaluated, the optimal degree of substitution of theSBE γ-CD that provides the greatest enhancement in solubility of BDP isDS=3.4, and solubility decreases almost linearly as the degree ofsubstitution increases. This is true for both the 24 hr and 5 dayequilibration times. In terms of BDP solubilization with SAE-CD:SBE(3.4)γ-CD>SBE(5.2)γ-CD>SBE(6.1)γ-CD>SBE(7.5)γ-CD>γ-CD>CAPTISOL(SBE7-β-CD). The data is summarized in FIG. 5. Therefore, it has beendetermined that SAE-γ-CD cyclodextrin derivatives are unexpectedlybetter at solubilizing corticosteroids than are SAE-O-CD derivatives.Formulations based upon SAE-γ-CD are suitable for use in thecompositions of the invention.

Example 19

Determination of the phase solubility of budesonide in the presence ofSAE-CD and azelastine hydrochloride.

A stock solution of citrate buffer (3 mM, pH 4.5) was prepared. Stocksolutions of CAPTISOL in buffer having CAPTISOL present in the varyingconcentrations (10 mM, 20 mM, 30 mM, and 40 mM) were prepared by mixingappropriate amounts of CAPTISOL and the buffer stock solution. The stocksolutions of CAPTISOL in buffer were used to prepare stock solutions ofazelastine HCl/CAPTISOL/buffer having 1 mg/mL, 1.37 mg/mL, 1.96 mg/mL,or 2.74 mg/mL azelastine HCl. Budesonide (at a concentration of 2 mg/mL)was added to the various stock solutions of azelastineHCl/CAPTISOL/buffer and mixed and allowed to equilibrate at ambienttemperature for a period of four days. Any budesonide remainingsuspended in the solutions was removed by filtration and theconcentration of budesonide in each solution measured by HPLC asdescribed herein. The results are depicted in FIG. 11A.

The above procedure was repeated with 10 mM, 15 mM and 20 mM solutionsof SBE-γ-CD and only one concentration of azelastine HCl (2.74 mg/mL).The data are summarized in FIG. 11B.

Example 20

Exemplary compositions of the invention packaged in various multi-dosevolume metered dose pump spray devices and nebulizers are made toinclude the following ingredients in the amounts specified according tothe procedure below.

For a 50 μL For a 70 μL For a 100 μL 200 μL 5000 μL Spray Spray SprayAmpoule Ampoule Ingredient¹ Function (mg/mL) (mg/mL) (mg/mL) (mg/mL)(mg/mL) Mometasone Active Substance 1.0 0.71 0.50 1.00 0.1 FuroateOlopatadine Active Substance 13.3 9.5 6.65 26.6 1.3 HCl SBE γ-CDSolubilizer-Stabilizer 452/500 323/429 226/300 452/500 45.2/60Nominal/Practical amts Disodium Antioxidant 0.1 0.1 0.1 0.1 0.1 edetate,dihydrate Citric acid, Buffer 0.3 0.3 0.3 0.3 0.3 Sodium Buffer 0.5 0.50.5 0.5 0.5 citrate dihydrate Sterile water Solvent q.s. to 1.0 mL q.s.to 1.0 mL q.s. to 1.0 mL q.s. to 1.0 mL q.s. to 1.0 mL for injection,

To prepare the above formulation, the mometasone furoate and olopatadineHCl are dissolved using SBE(6.1) γ-CD and citrate buffer at about pH4.5. Vigorous mixing and sonication may be required for a day or moreunder an inert atmosphere to effect total dissolution. If after assayingthe solution it is determined to be below the desired target for theactive ingredients, additional active ingredient can be added to thesolution and stirring continued. Once both drugs have dissolvedcompletely in the CD solution, confirmed by assay, the product isfiltered using a 0.22 μm PVDF filter. The solution is then dispensedunder an inert atmosphere into a preservative free multidose containerfitted with a suitable pump spray or filled into blow-fill-seal LDPEcontainers for use in a suitable nebulizer or as a drop. Optionally,compositions could contain potassium sorbate present at a concentrationof about 1 mg/mL and or polysorbate 80 present at a concentration ofabout 0.005% and be filled in suitable multi dose containers and fittedwith a suitable metering pump spray device.

Each package contains approximately 120 doses plus an overfill asdefined herein. Suitable packages for the specified spray volumesinclude:

-   -   1. 50 μL Spray volume: 9 mL of composition in a 10 mL bottle;        for example 20242 02 001 diagnostic 6/8 amber glass type 1 400        20 neck finish bottle fitted with Nasal Spray Pump having a 50        μL dose volume, 20/400 screw closure, and 42.0 mm dip tube        length;    -   2. 70 μL Spray volume: 13 mL of composition in a 15 mL amber        glass bottle;    -   3. 100 μL Spray volume: 17 mL of composition in a 20 mL amber        glass vial;    -   4. 200 μL ampoule: a single blow-fill-seal LDPE (or comparable        substance ampoule used for nebulization;    -   5. 5000 μL ampoule: a single blow-fill-seal LDPE (or comparable        substance ampoule used for nebulization.

Example 21

Evaluation of the AERONEB GO nebulizer versus a RAINDROP nebulizer witha solution comprising budesonide, aqueous liquid carrier and SAE-CD.

The AERONEB GO nebulizer (AEROGEN Inc., Mountainview, Calif.) isdetailed in U.S. Pregrant Publication No. 2005-011514 to Power et al.(Application U.S. Ser. No. 10/833,932 filed Apr. 27, 2004), PCTInternational Publication No. WO 2005/009323 to Aerogen, Inc. et al.(PCT Application No. PCT/US2004/021268 filed Jul. 6, 2004), and EuropeanApplication No. EP 16426276, the entire disclosures of which are herebyincorporated by reference.

The RAINDROP nebulizer is available from Nellcor (Tyco Healthcare).

The solution of the invention used for this study was prepared accordingto Example 28.

Characterization of droplet size distribution of an aerosolized solutionusing a cascade impactor was determined according to Example 26.

Determination of total drug output and drug output rate from a nebulizercontaining a liquid of the invention was determined according to Example27.

Example 22

Evaluation of the pulsating membrane nebulizer of U.S. Pat. No.6,962,151 with a solution comprising budesonide, aqueous liquid carrierand SAE-CD. Inertial Impaction Characterization of Tc^(99m)-DTPALabelled CAPTISOL-ENABLED Budesonide Aerosols Generated via a PariElectronic Nebulizer

The nebulizer detailed in U.S. Pat. No. 6,962,151, is also described inPCT International Application No. PCT/US00/29541 filed Oct. 27, 2000,and U.S. application Ser. No. 11/269,783 filed Nov. 7, 2005.

Aerosol characterization was conducted by standard in vitro inertialimpaction tests using an Andersen Cascade Impactor (ACI). Technetium-99m(^(99m)Tc), in the form of diethylenetriaminepenta-acetic acid (DTPA, GEHealthcare), was added to the CAPTISOL-ENABLED Budesonide Nasal Solution(CEBUD). The suitability of ^(99m)Tc-DTPA to function as a surrogate forbudesonide in CEBUD preparations was validated in the course of anearlier clinical trial. Preparation of the budesonide solutionformulation for testing was conducted as per the description below. Itwas calculated that approximately 10 MBq of ^(99m)Tc should be added tothe budesonide formulation (11.05 g) on the day of testing, in order toprovide sufficient activity for in vitro imaging.

Two Pari electronic vibrating membrane nebulizers were used. At the coreof this electronic nebulizer is a stainless steel membrane withthousands of laser drilled holes. Laser drilling allows flexibility tocustomize particle size, ensure reproducibility, and maintain a highoutput rate with smaller particles. The perforated membrane is vibratedat high frequencies in a resonant “bending” mode which yields highparticle output rates. The nebulizer provides rapid drug delivery,efficiency, ideal particle sizing, low residual volume, and optimalperformance matched to the drug formulation (See Rajiv Dhand,Respiratory Care 2002;(12): 1406-1416). Approximately 0.5 mL of drugsolution was loaded and subsequently delivered via each nebulizer on 3separate occasions. Runs 1, 3 and 5 were conducted with Device 1 andruns 2, 4 and 6 were conducted with Device 2.

Pre-Dose

On each occasion, prior to dose delivery, the filled nebulizer wasimaged for 60 seconds on Head I of the dual head gamma camera (Axis,Philips Medical Systems). Also, the nebulizers were weighed before andafter addition of the budesonide formulation.

Inertial Impaction Testing

The nebulizer was positioned at the USP (United States Pharmacopoeia)inlet of the ACI and a flow rate of 28.3 L/min was drawn through theimpactor using a vacuum pump. Flow through the impactor was startedprior to activation of the electronic nebulizer. A stopwatch was used inorder to measure the duration of dose delivery.

The ACI test conditions were the same as those used for Pari LC Plusair-jet nebulizer evaluation in the course of the earlier clinicalstudy.

Following deposition the USP throat was removed from the ACI and imagedfor 120 seconds. The collection plates were removed from the impactorand placed on Head I of the gamma camera and imaged for 120 seconds. Theplates were subsequently washed and dried before conduct of furtherimpaction tests.

Post-Dose

On each occasion, the nebulizer weight was recorded after delivery ofthe dose. The nebulizer was imaged as described below.

Image Processing

A rectangular ROI was applied to image to the nebulizer pre-dose. ThisROI was then re-applied to image the nebulizer after dose delivery.

A rectangular ROI was also applied to the USP Inlet image.

A circular ROI was drawn around collection plate 0, copied and placedaround plate 1. This was repeated for plates 2-7 and the filter. Arectangular ROI was also drawn to assess the background counts. Rawcounts were corrected for background activity and adjusted to counts perminute (cpm).

Aerosol performance is characterized in the table, in terms of the fineparticle fraction (FPF) i.e. % emitted dose with a particle size <5.8μm, mass median aerodynamic diameter (MMAD), geometric standarddeviation (GSD) and the nebulization delivery time.

CEBUD Preparation

The expelled contents of five PULMICORT RESPULES (1 mg/mL) were combinedtogether. CAPTISOL (165 mg) on a dried basis was added per Respule usedto the combined contents of the commercial suspension to provide aCAPTISOL concentration of about 7.5% w/v.

The mixture was vortexed briefly to disperse and dissolve the CAPTISOL.Then placed on a roller-bed mixer and allowed to mix for two-four orseveral hours. Aliquots of the equilibrated mixture were used to recoverany budesonide retained in the original Respule container, and therecombined together. The mixture was then further equilibrated overnight(˜20 hours) on the roller-bed mixer. After visually checking that allthe suspended solids had dissolved, the required volume of 99mTc-D5PA/saline solution (provided by Medical Physical Department, UHW)was added. So about 180 μl of the Radiolabel solution was added to theCAPTISOL-ENABLED Budesonide Nasal Solution and vortexed briefly.

Example 23

Determination of the phase solubility curve for corticosteroiddissolution with SAE-CD.

The solubility of corticosteroid solutions containing SAE-CD wasdetermined by HPLC chromatography of aliquots from equilibrated filteredor centrifuged corticosteroid solutions as follows.

SAE-CD/steroid solutions were prepared by weighing dry solids of SAE-CD(to provide 0.04 molar) and excess steroid drug (6 mg/mL) together intoa screw-capped vial. A volume of water was aliquoted to each vial(separate vial for each steroid). Intrinsic solubility was determined byweighing excess steroid (6 mg/mL) and adding a volume of water in theabsence of CD. Vials were capped, initially vortexed and sonicated.Vials were then placed on a roller-mixer (model: SRT2; Manufacturer:Stuart Scientific; Serial number: R000100052) or rocker/mixer (Model:LabQuake; Manufacturer: Barnstead/Thermolyne; Serial number:1104010438202). Higher excesses of solid steroid (up to 10 mg/mL) werethen added to any vial where the liquid contents clarified overnight(e.g. prednisolone, hydrocortisone, and prednisone). Samples were rolledand mixed on the roller or rocker for 72 hours. At various times duringthe equilibration, samples were additionally vortexed or sonicatedbriefly (up to 30 minutes). After the designated equilibration time,samples were filtered (0.22 μm, 25 mm, Duropore—PVDF, manufacturer:Millipore) into clean vials except for the intrinsic solubility samplefor Beclomethasone Dipropionate which was centrifuged and thesupernatant transferred to a clean vial. Samples were analyzed byconventional HPLC methods. The results are detailed below.

[Fluticasone] × [Mometasone] × 10⁵M 10⁵M [Triamcinolone as non As non[Budesonide] × acetonide] × -CD [CD] M propionate esterified furoateesterified 10⁵M 10⁵M H₂O NA 0.39 0.16 1.82 0.00 6.59 3.56 β 0.015M 1.3612.9 81.3 (SBE)_(6.7) β 0.0465 5.41 126.4 16.4 121.7 254.8 457.0 0.09507.99 215.9 31.1 226.1 428.1 1023.3 (SBE)_(2.4) β 0.04 1.70 12.8 0.082.46 (SPE)₇ β 0.04 1.05 93.9 7.23 122.4 0.08 2.12 151.2 10.8 223.3 241.6

Solubility of Selected Steroids Enhanced by Alpha-Cyclodextrins

[Fluticasone] × 10⁵M [Mometasone] × 10⁵M [Triamcinolone as non non[Budesonide] × acetonide] × -CD [CD] M propionate esterified as furoateesterified 10⁵M 10⁵M H₂O NA 0.39 0.16 1.82 0.00 6.59 3.56 A 0.04 0.008.4 0.08 0.27 28.5 (SBE)₇ α 0.04 8.37 30.1 55.0 348.1 0.08 11.4 35.5116.9 597.9

Solubility of Selected Steroids Enhanced by Gamma-Cyclodextrins

[Fluticasone] × [Mometasone] × 10⁵M 10⁵M [Triamcinolone as non as non[Budesonide] × acetonide] × -CD [CD] M propionate esterified furoateesterified 10⁵M 10⁵M H₂O NA 0.39 0.16 1.82 0.00 6.59 3.56 Γ 0.035 73.514.1 2.71 10.1 197.8 0.1 22.1 82.2 65.8 0.09 4.1 138.6 (SBE)_(5.2) γ0.04 79.12 375.8 0.1 215.3 1440.4 93.9 889.2 861.6 (SBE)_(6.1) γ 0.0451.82 575.6 41.5 841.1 306.6 1059.5 0.08 120.8 949.0 92.9 1423.1 698.82386.1 (SBE)_(9.7) γ 0.04 54.5 0.075 103.1 895.0 94.0 889.6 453.4(SPE)_(5.4) γ 0.04 71.7 759.5 28.7 400.9 0.08 140.1 1387.8 51.3 1467.1774.2

The phase solubility data, determined according to this example orExample 18, can be used to determine the molar ratio of SAE-CD tocorticosteroid necessary to dissolve the corticosteroid in an aqueousmedium. The table below details relevant molar ratio data.

Approximate Molar Ratio at Saturated Solubility of Corticosteroid*Corticosteroid SAE-CD (SAE-CD:corticosteroid) Beclomethasonedipropionate SAE-β-CD 358 Beclomethasone dipropionate SAE-γ-CD 86Budesonide SAE-β-CD 16 Budesonide SAE-γ-CD 13 (SBE6.1), 10.8 (SBE5.2),10.1 (SPE5.4) Budesonide SAE-α-CD 12 X-1 corticosteroid SAE-β-CD 190 X-1corticosteroid SAE-γ-CD 1390 Flunisolide SAE-β-CD 16 FlunisolideSAE-γ-CD 9 Fluticasone SAE-β-CD 32 Fluticasone Propionate SAE-β-CD 797Fluticasone Propionate SAE-γ-CD 78 Fluticasone Propionate SAE-α-CD 501Hydrocortisone SAE-β-CD 1.6 Hydrocortisone SAE-γ-CD 1.8Methylprednisolone SAE-β-CD 5.7 Methylprednisolone SAE-γ-CD 3.4Mometasone SAE-α-CD 73 Mometasone SAE-β-CD 33 Mometasone furoateSAE-α-CD 141 Mometasone furoate SAE-β-CD 274 Mometasone furoate SAE-γ-CD101 Prednisolone SAE-β-CD 2.2 Prednisolone SAE-γ-CD 2 PrednisoneSAE-β-CD 2.2 Prednisone SAE-γ-CD 3.2 Triamcinolone acetonide SAE-β-CD8.8 Triamcinolone acetonide SAE-γ-CD 3.8 *This value was determined inthe presence of SAE-CD under the conditions detailed in Example 18 orthis example.

Example 24

Exemplary compositions of the invention packaged in various multi-dosevolume metered dose pump spray devices are made to include the followingingredients in the amounts specified according to the procedure below.

50 μL 70 μL 100 μL 200 μL 5000 μL Spray Spray Spray Ampule AmpuleIngredient¹ Function (mg/mL) (mg/mL) (mg/mL) (mg/mL) (mg/mL) FluticasoneActive Substance 1.0 0.71 0.50 1.00 0.1 Propionate Cetirizine HCl ActiveSubstance 22 15.7 11 11 0.22 SBE γ-CD Solubilizer- 452/500 323/429226/300 452/500 45.2/60.0 Stabilizer nominal/practical DisodiumAntioxidant 0.1 0.1 0.1 0.1 0.1 edetate, dihydrate Citric acid, Buffer0.3 0.3 0.3 0.3 0.3 Sodium citrate Buffer 0.5 0.5 0.5 0.5 0.5 dihydrateSterile water Solvent q.s. to 1.0 mL q.s. to 1.0 mL q.s. to 1.0 mL q.s.to 1.0 mL q.s. to for injection, 1.0 mL

To prepare the above formulation, the fluticasone propionate andcetirizine HCl are dissolved using SBE γ-CD and citrate buffer at aboutpH 4.5 to 5. Vigorous mixing and sonication may be required for a day ormore under an inert atmosphere to effect total dissolution. If afterassaying the solution it is determined to be below the desired targetfor the active ingredients, additional active ingredient can be added tothe solution and stirring continued. Once both drugs have dissolvedcompletely in the CD solution, confirmed by assay, the product isfiltered using a 0.22 μm PVDF filter. The solution is then dispensedunder an inert atmosphere into a preservative free multidose containerfitted with a suitable pump spray or filled into blow-fill-seal LDPEcontainers for use in a suitable nebulizer or as drops. Optionally,compositions can contain potassium sorbate present at a concentration ofabout 1 mg/mL and/or polysorbate 80 present at a concentration of about0.005% and be filled in suitable multi-dose containers and fitted with asuitable metering pump spray device.

Suitable packaging is detailed in Example 20. The packaging can be in apreservative free pump spray system such as the Advanced PreservativeFree system from Pfeiffer, or the Freepod from Valois, or in a singleuse pump spray device such as the Pfeiffer Bidose System or UnitdoseSystem. For the nebulized solutions the Kurve ViaNase™ or anothercomparable nasal nebulizer device could be used.

Example 25

A composition comprising a corticosteroid and antifungal agent isprepared as follows.

The following ingredients are combined in the amounts indicated.

1 mL vial 2 mL vial 5 mL vial Ingredient Function (mg/mL) (mg/2 mL)(mg/5 mL) Budesonide Active Substance 0.05 0.1 0.25 Voriconazole ActiveSubstance 10 20 50 CAPTISOL Solubilizer/Stabilizer 165 330 825 DisodiumAntioxidant 0.1 0.2 0.5 edetate dehydrate Citric acid, Buffer 0.3 0.61.5 Sodium citrate Buffer 0.5 1.0 2.5 dihydrate Sterile water forSolvent q.s. to 1.0 mL q.s. to 2.0 mL q.s. to 5.0 mL injection* *Thewater is removed during processing by lyophilization or spray drying orother suitable drying technique to form a powdered composition. Hencethe contents are reconstituted just prior to use.

Example 26

A composition comprising a corticosteroid and antimicrobial agent isprepared as follows.

Method A. For 50 μL For 70 μL For 100 μL 200 μL 5000 μL Spray SpraySpray Ampoule Ampoule Ingredient Function (mg/mL) (mg/mL) (mg/mL)(mg/mL) (mg/mL) Budesonide Active Substance 0.64 0.46 0.32 0.16 0.0064Azithromycin Active Substance 0.4 0.29 0.2 0.1 0.004 CAPTISOLSolubilizer/ 64 46 32 16 0.64 Stabilizer Disodium Antioxidant 0.1 0.10.1 0.1 0.1 edetate dehydrate Citric acid, Buffer 0.3 0.3 0.3 0.3 0.3Sodium Buffer 0.5 0.5 0.5 0.5 0.5 citrate dehydrate Sterile waterSolvent q.s. to 1.0 mL q.s. to 1.0 mL q.s. to 1.0 mL q.s. to 1.0 mL q.s.to 1.0 mL for injection

To prepare the above formulation the budesonide and azithromycin isdissolved using CAPTISOL and citrate buffer at about pH 4.5. Vigorousmixing and sonication may be required for a day or more under an inertatmosphere to effect total dissolution. If after assaying the solutionit is determined to be below the desired target for the activeingredients, additional active ingredient can be added to the solutionand stirring continued. Once both drugs have dissolved completely in theCD solution, confirmed by assay, the product is filtered using a 0.22 μmPVDF filter. The solution can then be dispensed under an inertatmosphere into a preservative free multidose container fitted with asuitable pump spray or filled into blow-fill-seal LDPE containers foruse in a suitable nebulizer or as a drop. Optionally, compositions cancontain potassium sorbate present at a concentration of about 1 mg/mLand/or polysorbate 80 present at a concentration of about 0.005% and befilled in suitable multi-dose containers and fitted with a suitablemetering pump spray device. Suitable packaging is detailed in Example24.

Method B. 1 mL vial 2 mL vial 5 mL vial Ingredient Function (mg/mL)(mg/mL) (mg/mL) Budesonide Active Substance 0.05 0.1 0.25 AzithromycinActive Substance 10 20 100 CAPTISOL Solubilizer/Stabilizer 7.5 15 37.5Disodium Antioxidant 0.1 0.2 0.5 edetate dihydrate Citric acid, Buffer0.3 0.6 1.5 Sodium citrate Buffer 0.5 1.0 2.5 dihydrate Sterile waterfor Solvent q.s. to 1.0 mL q.s. to 2.0 mL q.s. to 5.0 mL injection* *Thewater is removed during processing by lyophilization or spray drying orother suitable drying technique to prepare a powdered composition. Hencethe contents are reconstituted just prior to use.

Example 27

A powdered composition of budesonide and azelastine can be prepared asfollows.

The following ingredients are combined in the amounts indicated toprepare an active composition.

Amount needed Ingredient Function (mg/mL) Budesonide Active Substance0.457 Azelastine HCL Active Substance 1.96 CAPTISOLSolubilizer/Stabilizer 100 Disodium Antioxidant 0.1 edetate, (0.05 to0.15) dihydrate Citric acid Buffer 0.3 Sodium citrate Buffer 0.5dihydrate (0.45 to 0.55) Sterile water Solvent q.s. to 1 mL forinjection,* *Water is removed during processing by lyophilization orspray drying or other suitable technique. If necessary, theconcentration used for the processing method can be adjusted to assistin achieving the desired particle size.

The budesonide and azelastine HCL are dissolved in the CAPTISOL andcitrate buffer (about pH 4.5) using a vigorous stirring method. Duringprocessing and packaging the liquid product is further protected usingan inert atmosphere. In addition the water used for the process may besparged with nitrogen to reduce oxygen. Once both drugs are dissolved,the solution is lyophilized using a suitable method that will produce astable, uniform cake. The lyophilized product is then sized to obtain anaverage particle size of Dv(50) between 10-100 μm or about 65 μm as theactive composition.

The active composition can be mixed with a bulking agent to prepare apowder formulation for administration with an administration devicecapable of emitting and nasally delivering the powder. The powderformulation can be prepared according to the table below.

20 mg Powder 50 mg Powder Ingredient Function Nasal Aerosol NasalAerosol Actives Active Substances 7.225 mg 7.225 mg Composition(Includes: (0.032 mg, (0.032 mg, (see below) budesonide, 0.137 mg) 0.137mg) azelastine) Lactose Diluent/Bulking 12.775 mg 42.775 mg Agent

The following procedure can be used. A bulking agent, such as lactosesuitable for inhalation (Lactohale®), is dry mixed with the sizedlyophilized product to provide a total administered amount of 20 to 50mg as needed for a unit dose powder nasal spray such as the Monopowder(Valois) or DirectHaler™ (DirectHaler).

Example 28

Preparation of a liquid formulation comprising SAE-CD and budesonide,optionally containing TWEEN.

A 3 mM citrate buffer at pH 4.5 was added to 2 grams of CAPTISOL and 25mg of budesonide in a serum vial to make the final volume 10 mL. Thesuspension was well mixed by vortexing and sonication. A 20% stocksolution of CAPTISOL without budesonide was also prepared in 3 mMcitrate buffer. These mixtures, along with the buffer were sealed inseparate vials and autoclaved using the 20-minute hold at 121° C. cycle.HPLC analysis of the clear budesonide solution showed the concentrationwas 2100 μg/mL. The 20% CAPTISOL stock solution was used to dilute thesample to 2000 μg/mL. A portion of the above resulting solution wasoptionally diluted with an equal volume of the 3 mM citrate buffer. HPLCanalysis showed the final concentration was 990 μg of budesonide/mL.

The TWEEN could be added to the above solution as follows. A solution of0.02% TWEEN was prepared with the autoclaved buffer only solution toform a TWEEN stock solution for use as a diluent for the abovesolutions. The dilutions for the 10% CAPTISOL/1 mg/mL budesonide weredone by weight. Approximately 9 grams of the 20% captsiol/2000 μg/mL wasmixed with ˜9 grams of either the autoclaved buffer only solution or theautoclaved buffer/0.02% TWEEN solution. These solutions were well-mixed,filtered and reassayed by HPLC.

The budesonide concentrations of the above formulations were found to be986 μg/mL for the solution without TWEEN and 962 μg/mL for the solutionwith TWEEN.

The solutions can be nebulized with any nebulizer; however, with an AERxnebulizer, an initial sample volume of 50 μl can be used. Administrationof this solution with the nebulizer makes it feasible for a therapeuticdose to be administered to a subject in a single puff (a single fullinspiration by a subject) via nebulization.

Example 29

Preparation and dissolution of a lyophilized formulation comprisingSAE-CD and budesonide.

An excess of budesonide, 3.5 mg/mL, was added to 3 L of 30% CAPTISOL in3 mM citrate buffer containing 0.1 mg/mL EDTA. After mixing for 2 days,an additional 1 mg/mL budesonide was added and equilibrated anadditional 4 days. The preparation was filtered through a 0.22 μDuraporefilter and placed in three stainless steel trays in a freeze dryer. Thesolution was frozen at −30° C. for one hour and lyophilized over 30hours to remove essentially all the water. The lyophile was powdered,screened and the powder transferred to a plastic bottle. The finalcomposition contained 8.2 mg budesonide per gram of powder.

When approximately 65 mg of powder was added to 2 mL of water, anessentially clear solution containing the same amount of budesonide asin the reference suspension product was rapidly obtained.

Example 30

Preparation of an aqueous liquid formulation comprising SAE-CD, ethanoland budesonide.

CAPTISOL/Ethanol solutions were prepared by making a stock CAPTISOLsolution at 22.2% (˜0.1 M) w/v which was diluted with either ethanol orwater in varying amounts to create four solutions of 0, 1, 2, 5% ethanoland about 20% w/v CAPTISOL. CAPTISOL/Ethanol/Budesonide solutions wereprepared by adding dry budesonide (2.5 mg/mL) to a volume of theprepared CAPTISOL/ethanol solutions and then these were equilibrated ona Labquake for 72 hours. These solutions were filtered (Duropore syringefilters) and analyzed by HPLC to determine the concentration (μg/mL) ofbudesonide dissolved in the formulation.

Example 31

An electronic tongue study can be conducted as follows to determine theeffectiveness of SAE-CD at masking the bitter taste of an active agent,such as azelastine.

The e-tongue (Astree II, Alpha M.O.S., Toulouse, France) has been usedto demonstrate an increasing change in the taste of azelastine HClsolution upon the addition of increasing amounts of CAPTISOL. Solutionscontaining 2 mg/mL azelastine HCL in 3 mM, pH=4 citrate buffer, withdifferent amounts of CAPTISOL were prepared. The e-tongue uses aseven-sensor probe assembly to detect dissolved organic and inorganiccompounds. The probes consist of a silicon transistor with proprietaryorganic coatings, which govern the probe's sensitivity and selectivity.Measurement is potentiometric, with readings taken against an Ag/AgClreference electrode. Samples are placed in an autosampler carrouselwhere the electrodes are introduced into each sample. Each probe iscross-selective to allow coverage of full taste profile. The systemsamples, quantifies, digitizes, and records potentiometer readings.Taste cognition happens not in the probe, but in the computer, where thee-tongue's statistical software interprets the sensor data into tastepatterns. The distance from the azelastine HCL in buffer to thesolutions containing 5%, 10% or 15% CAPTISOL were 334.03, 418.96, and491.76 respectively indicating a large change in taste.

Example 32

To investigate how the incorporation of CAPTISOL at 5% w/v intoPULMICORT RESPULES impact performance of different types of nebulizers.

The emitted dose of budesonide from four different nebulizers (PARI LCPLUS (air jet), OMRON MICROAIR NE-U22, AIRSEP MYSTIQUE(ultrasonic),AEROGEN AERONEB) was determined. The package insert-approved Pari airjet system was used as the benchmark to judge performance of the othernebulizers. The emitted dose was from 1.25 to 3.7 times higher whenCAPTISOL was added to the budesonide suspension. The Emitted dose (ED)was determined by:

-   -   1) Drawing the nebulized formulations through a 300 mL glass        filter apparatus at 15 l/min, and collecting drug on double or        triple layers of glass fiber depth filter and the interior        walls. Collection was stopped every two minutes, the budesonide        quantitatively recovered, and filters were changed to prevent        filter saturation or alterations in airflow. Budesonide recovery        was quantified by HPLC; and/or    -   2) Summing the amount of budesonide on the cascade impactor        stages after nebulization.

The results are detailed below. (ND means “not determined.)

Total Delivered (ED) Total Delivered (ED) (μg, mean & SD), (μg, mean &SD), Formulation Filter¹ Impactor² Pari LC Plus (Air Jet) Listed in thePulmicort package insert Pulmicort 171.5 ± 6.3  137.8 ± 14.9 Pulmicort +5% 247.4 ± 11.3 172.4 ± 6.6  CAPTISOL Omron MicroAir NE-U22 Pulmicort179.9 ± 17.2 168.8 ± 30.1 Pulmicort + 5% 380.1 ± 8.5  349.6 ± 10.0CAPTISOL AirSep Mystique (Ultrasonic) Pulmicort 32.9 ± 6.4 ND*Pulmicort + 5% 120.8 ± 19.6 ND* CAPTISOL Aerogen AeroNeb Pulmicort 90.7± 4.5 ND* Pulmicort + 5% 301.2 ± 19.5 ND* CAPTISOL

Example 33

A clinical trial was conducted to evaluate the performance of aformulation of the invention in the treatment of nasal symptoms andnon-nasal symptoms caused by exposure of subjects to an allergen.

Three aqueous based formulations were made: Solution A—comprisingCAPTISOL, budesonide and aqueous liquid carrier; Suspension B—comprisingRHINOCORT AQUA suspension of budesonide in aqueous liquid carrier; andSolution C (placebo)—comprising buffered saline. Solution A was made bymixing two NEBUAMPS (500 μg/mL nominal) to a bottle containing 348 mgCAPTISOL, followed by mixing overnight to form a solution containing 424μg/mL of budesonide and 75 mg/mL of CAPTISOL in a total volume of 4.4mL. Solution B was purchased and used as is (32 μg of budesonide perspray) using a spray volume of 50 μl with the supplied valve. Bottlescontaining Solutions A and C were equipped with a 70 μl Pfeiffer sprayvalve. Bottles were masked prior to use. Solutions A and B wereadministered at a dose of 32 μg per spray. Dosing of Solutions A or C orSuspension B was as a single spray in each nostril.

The bulk solution concentration of budesonide in Solution A ranged from418-439 μg/mL with an average of 432±6 μg/mL. Based upon HPLC analysis,each spray of Solution A contained about 31 μg of budesonide.

Clinical Protocol.

A randomized, double-blind, placebo-controlled, single-center, three-waycross-over study was conducted to compare the relative efficacy ofbudesonide, administered via nasal spray using Solution A and SolutionB, with Solution C as the placebo control, in the treatment of SAR in anenvironmental exposure chamber. Sixty five subjects were enrolled in thestudy and exposed to ragweed pollen using an EEC model. The total nasalsymptom score (TNSS) and total non-nasal symptom score (TNNSS) for eachsubject was determined. A graphical summary of the study protocol isdepicted in FIG. 7. Patients were exposed to 3000 to 4000 particles percubic meter of ragweed pollen using an Environmental Exposure Chambermodel of the disease. After the initial exposure to pollen, patientswere then treated with Solution A (CAPTISOL, budesonide, aqueous carriersolution), Suspension B (RHINOCORT AQUA: budesonide, aqueous carriersuspension), or Solution C (saline placebo) in a crossover design. Eachpatient remained in the chamber exposed to pollen and rated their nasalsymptom and their non-nasal symptoms over a period of 10 hours.

The primary objective of the study was to compare the relative efficacyof budesonide administered via CAPTISOL-ENABLED Budesonide nasalsolution and RHINOCORT AQUA in patients with SAR exposed to controlledragweed pollen using an EEC model. Secondary objectives of the studywere to: 1) assess the onset of action of Solution A and Solution B ascompared to placebo; 2) compare the tolerance of each as determined bypatient questionnaire and adverse events recorded; and 3) compare theeffect of the three solutions on the EEC-specific Quality of LifeQuestionnaire (EEC-QOLQ).

This was a randomized, double-blind, placebo-controlled, single-center,3-way cross-over study with three periods of two-four 3 h priming visitsfollowed by a 12 h treatment visit. Following an initial 30-minuteexposure to ragweed pollen in the EEC, the patients evaluated four nasalsymptoms (itchy nose, runny nose, congestion and sneezing) and fournon-nasal symptoms (itchy/gritty eyes, tearing/watery eyes, red/burningeyes, and itchy ears/palate) every 30 minutes for 1.5 hours to determineadequate baseline symptoms. Each symptom was rated on a scale of 0 to 3(none, mild, moderate, and severe). Patients who met the predeterminedminimum TNSS score of 6 out of a maximum of 12, including a minimumscore of 2 out of 3 for runny nose on the last two diary cards prior totreatment, were randomized to receive one of three treatments in adouble-blind manner. Patients who did not meet the predetermined TNSSwere not dosed and were withdrawn from the study.

Following administration of the study drug, the patients were asked toassess their NSS (nasal symptom score), OSS (ocular symptom score), andNNSS (non-nasal symptom score) at 15, 30, 45, 60, 90 and 120 minutespost dosing; then every hour up to 10 hours post-dose. TSS was the sumscore of 4 nasal symptoms: runny-, itchy-, stuffy-nose and sneezing; and4 non-nasal symptoms: 3 ocular symptoms (TOSS): redness, itching,tearing and 1 non-nasal, non-ocular: itchy ears/palate. During theentire time the patients were in the EEC, they were exposed to ragweedpollen at a concentration of 3500±500 particles per m³.

Patients rated nasal symptoms (rhinorrhea, nasal congestion, nasalitchiness, and sneezing) and non-nasal symptoms (itchy/gritty eyes,tearing/watery eyes, red/burning eyes, itchy ears and palate). See FIGS.6A-6C and 6F. Area under the curve (AUC) was calculated based on themean change from baseline for TNSS, TNNSS and TSS and was compared usinganalysis of covariance. See FIGS. 6G, 6H and 6I. Secondary efficacyassessed the onset of action of CAPTISOL-ENABLED Budesonide compared toRHINOCORT AQUA and placebo. The TNSS and TNNSS scores were then totaled.This data was evaluated to determine efficacy and speed of action.

The effect of CAPTISOL-ENABLED Budesonide compared to placebo on ocularsymptoms was determined. The mean AUC for itchy/gritty eyes demonstratedsignificant efficacy of CAPTISOL-ENABLED Budesonide (−4.21±7.00) overplacebo (−2.10±6.62) (p=0.042). The mean AUC for tearing/watery eyesalso demonstrated significant efficacy of CAPTISOL-ENABLED Budesonide(−3.05±7.08) over placebo (−1.67±6.66) (p=0.047). UnlikeCAPTISOL-ENABLED Budesonide, micronized suspension (RHINOCORT AQUA) didnot demonstrate significant efficacy compared to placebo in ocularsymptoms. The effect of CAPTISOL-ENABLED Budesonide compared to placeboon itchy/gritty eyes was greatest at timepoints 1.5, 2 and 3 hrpost-dose with changes from baseline of −0.70±0.84 (p=0.031), −0.67±0.83(p=0.020) and −0.58±0.83 (p=0.044), respectively. Similarly, the effecton tearing/watery eyes was greatest at 3 hr with changes from baselineof −0.55±0.89 (p=0.004) and the effect on red/burning eyes was greatestat 0.5, 1 and 2 hr with changes from baseline of −0.47±0.74 (p=0.010),−0.58±0.88 (p=0.030) and −0.55±0.97 (p=0.022), respectively. Based onthe mean change from baseline, the onset of action for CAPTISOL-ENABLEDBudesonide for improvement in itchy/gritty eyes was 1.5 hr.CAPTISOL-ENABLED Budesonide also demonstrated significance onitchy/gritty eyes over RHINOCORT AQUA at 0.5 hr (p=0.008) and 0.75 hr(p=0.014). The data for these symptoms is summarized in FIGS. 6D-6E.

In FIG. 6F, the MCFB in TSS was greater at hours 0.25, 0.5, 0.75, 1.0,and 1.5 for CAPTISOL-ENABLED Budesonide (−2.33, −4.01, −4.30, −4.57,−4.77 and −4.86, respectively) than for RHINOCORT AQUA (−1.5, −2.34,−2.95, −3.43, −4.03, and −3.91, respectively) with an onset of action of0.5 h compared to 4 h onset for RHINOCORT AQUA.

The mean AUC TNSS was significant for CAPTISOL-ENABLED Budesonide(−18.02±22.7) versus placebo (−11.12±23.1) (p=0.036). Likewise, AUC TNSSfor RHINOCORT AQUA was −18.23±27.2 versus placebo at −11±23.1 At 0.25 h,0.5 h and 0.75 h, the mean change from baseline TNSS was greater forCAPTISOL-ENABLED Budesonide (−1.22, −2.11, −2.27 respectively) than forRHINOCORT AQUA (−0.87, −1.44, −1.73, respectively) with an onset ofaction for ocular symptoms at 0.5 h. RHINOCORT AQUA had no onset ofaction for ocular symptoms. Overall TNNSS AUC was significant (p=0.012)for CAPTISOL-ENABLED Budesonide (mean decrease of −16.61±27.3) comparedto placebo (−7.62±24.0) (p values <0.05). Of note, at 0.5 h, 0.75 h and1 h, the changes from baseline for the CAPTISOL-ENABLED Budesonide were−1.90±2.41, −2.03±2.92 and −2.41±3.11, respectively (all p values <0.05compared to RHINOCORT AQUA and placebo). The onset of action ofCAPTISOL-ENABLED Budesonide versus RHINOCORT AQUA and placebo wassignificantly different at 0.5 h-1 h (p values <0.05). No deaths orclinically significant adverse events were reported in this study. TheCAPTISOL-ENABLED Budesonide reduced TOSS versus placebo (−11.40±20.5 vs−5.38±19.0 p<0.05) while RHINOCORT AQUA did not (−8.57±23.1). Further,each ocular symptom of itchy/gritty eyes and tearing/watery eyesdemonstrated significant efficacy of CAPTISOL-ENABLED Budesonide overplacebo while RHINOCORT AQUA did not for any ocular symptom. The onsetof action for CAPTISOL-ENABLED Budesonide on TOSS was 1.5 hr. Theaverage TOSS is shown as a function of time in FIG. 6C.

The data are depicted in FIGS. 6A-6G and summarized in the table below.

CE- Budesonide Nasal RHINOCORT Time Solution AQUA Placebo Point (N = 65)(N = 65) (N = 65) (hour) Mean SE Mean SE Mean SE 0 0 0 0 0.25 −1.22 0.32−0.87 0.26 −0.85 0.25 0.5 −2.11 0.32 −1.44 0.32 −1.33 0.32 0.75 −2.270.35 −1.73 0.33 −1.72 0.36 1 −2.16 0.36 −2 0.36 −1.84 0.36 1.5 −2.370.34 −2.25 0.39 −1.78 0.34 2 −2.48 0.34 −2.32 0.41 −1.79 0.39 3 −2.140.35 −2.43 0.42 −1.67 0.36 4 −2.3 0.37 −2.1 0.4 −1.21 0.36 5 −1.81 0.35−1.94 0.43 −1.22 0.37 6 −1.56 0.34 −1.63 0.41 −0.98 0.33 7 −1.65 0.33−1.73 0.44 −0.93 0.33 8 −1.76 0.35 −1.9 0.45 −0.65 0.3 9 −1.59 0.34−1.62 0.44 −0.62 0.34 10 −1.3 0.35 −1.43 0.41 −0.61 0.32

The table below includes a summary of the TNNSS data for the study.

CE- Budesonide Nasal RHINOCORT Time Solution AQUA Placebo Point (N = 65)(N = 65) (N = 65) (hour) Mean SE Mean SE Mean SE 0 0 0 0 0.25 −1.11 0.31−0.63 0.28 −0.48 0.24 0.5 −1.9 0.3 −0.9 0.33 −1.02 0.3 0.75 −2.03 0.37−1.22 0.36 −1.16 0.33 1 −2.41 0.39 −1.43 0.38 −1.55 0.37 1.5 −2.4 0.38−1.78 0.42 −1.48 0.36 2 −2.38 0.39 −1.59 0.41 −1.19 0.35 3 −2.11 0.37−1.89 0.44 −1.04 0.35 4 −1.76 0.39 −1.41 0.42 −0.92 0.35 5 −1.73 0.37−1.38 0.45 −0.73 0.36 6 −1.51 0.41 −1.14 0.42 −0.65 0.35 7 −1.38 0.44−1.14 0.44 −0.58 0.34 8 −1.43 0.44 −1.13 0.43 −0.68 0.36 9 −1.3 0.41−0.84 0.45 −0.36 0.34 10 −1.13 0.4 −0.68 0.44 −0.38 0.34

The efficacy, as determined from the area under the TNSS rating-timecurve (AUC), for Solution A and Suspension B was better than placebo.There was little difference in efficacy between Solution A andSuspension B although the median score for Solution A was better. Also,nasal itchiness trended better for Solution A than for Suspension B orSolution C.

The efficacy, based on TNNSS AUC, shows that Solution A was better thanSolution C, while Suspension B was equivalent to Solution C. Overall,Solution A was substantially better than Solution C in three out of thefour non-nasal categories and trended better than Solution C in thefourth non-nasal category.

The initial reduction in TNSS was greatest for Solution A. This showsthat the speed of action of Solution A was faster than either SuspensionB or Solution C. Even though it was faster, the reduction in TNSS lastedas long as Suspension B.

The Onset of Action in reducing TNNSS was determined to be 0.5 hours forSolution A. Suspension B never met the previously established criterion.

When comparing mean change from baseline TNSS values for the first threetime points (0.25 hr, 0.5 hr and 0.75 hr), the mean decrease in TNSS wasgreater for CAPTISOL-ENABLED Budesonide than for RHINOCORT AQUA.However, statistical significance for CAPTISOL-ENABLED Budesonide versusplacebo was only achieved for the 0.5 hr time point. WhileCAPTISOL-ENABLED Budesonide lowered TNSS after 0.25 hours, the criticallevel of significance when compared to placebo was not achieved for mostof the time points. See FIG. 8A. The chart for the onset of action forthe first three time points for TNNSS is set forth in FIG. 8B.

CAPTISOL-ENABLED Budesonide reduced non-nasal symptom scores at 30minutes. This effect was not observed with RHINOCORT AQUA. There was nosignificant difference in the efficacy of CAPTISOL-ENABLED Budesonideand RHINOCORT AQUA for the primary efficacy variable of TNSS. The meanAUC for TNSS illustrates a significant treatment effect for bothCAPTISOL-ENABLED Budesonide versus placebo and RHINOCORT AQUA versusplacebo. CAPTISOL-ENABLED Budesonide is a well tolerated, effectivetreatment for SAR.

EEC-QOLQ

The EEC-QOLQ consisted of the following questions by way of whichsubjects rated their overall symptoms before and after administration ofthe three solutions.

The EEC-RQOLQ consists of Non-nose/Eye Symptoms, Practical Problems, andEmotional domains to assess the QOL experienced by patients in the EEC.The higher the score, the worse patients feel. The Practical Problemsdomain is important in the EEC-RQOLQ as it assesses the need to rubnose/eyes and to blow nose repeatedly, thus having an impact on dailyactivity.

Baseline was defined as the QOL questionnaire administered prior to EECentry, after exposure in the EEC and after treatment. Comparisonsbetween treatments were completed using ANCOVA. The EEC-RQOLQ wasadministered at −0.75 hours pre-dose, and at 2, 6 and 10 hourspost-dose. Quality of life was improved in patients treated withCAPTISOL-ENABLED Budesonide compared to placebo in all domains. The meanchange from baseline in EEC-RQOLQ scores for CAPTISOL-ENABLED Budesonideversus placebo were, for each domain, respectively: Emotional: 2 h:−0.3; −0.1; 6 h: 0.1; 0.3; 10 h: 0.4; 0.4. Non-nose/Eye symptoms 2h:−0.1; 0.1; 6 h: 0.1; 0.3; 10 h: 0.3; 0.5. Practical Problems: 2 h:−0.9; −0.2 (p=0.008); 6 h: −0.5; 0.1 (p=0.016), 10 h: −0.3; 0.3(p=0.019). The effects of the three solutions on the EEC-QOLQ aresummarized in FIGS. 9A to 9C. Subjects receiving CAPTISOL-ENABLEDBudesonide demonstrated improved QOL in the Emotional Domain andPractical Problems Domain. There was no significant difference in RQLQbetween the two treatments at ay time point.

This study demonstrates that this EEC-RQOLQ is a good indicator of QOLin the EEC. Practical Problems is an important domain in the EEC-RQOLQas it assesses the need to rub nose/eyes and to blow nose repeatedly,thus having an impact on daily activity. QOL scores in this domain weresignificantly improved in patients treated with CAPTISOL-ENABLEDBudesonide compared to placebo.

Example 34

A clinical trial was conducted to evaluate the performance of acombination composition of the invention in the treatment of nasalsymptoms and non-nasal symptoms caused by exposure of subjects to anallergen.

Four aqueous based formulations were made: Solution A—comprisingCAPTISOL, budesonide, azelastine hydrochloride, and aqueous liquidcarrier; Suspension B-comprising RHINOCORT AQUA suspension of budesonidein aqueous liquid carrier; Solution C—comprising ASTELIN solution ofazelastine hydrochloride in aqueous liquid carrier, and Solution D(placebo)—comprising buffered saline. Solution A was made by mixingtwenty NEBUAMPS (500 μg/mL nominal) to a bottle containing 4.71 mgCAPTISOL and 87.6 mg azelastine hydrochloride followed by mixingovernight to form a solution containing 424 μg/mL of budesonide and 100mg/mL of CAPTISOL. A 4 mL portion of the solution was placed in asmaller bottle fitted with a spray valve. Solution B was purchased andused as is (32 μg of budesonide per spray) using a spray volume of 50 μlwith the supplied valve. Solution C was purchased, poured into a smallerbottle and used with the supplied valve. Bottles containing Solutions Aand D were equipped with a 70 μl Pfeiffer spray valve. Bottles weremasked prior to use.

Clinical Protocol.

A Randomized, Double-Blind, Placebo-Controlled, Three-Way Cross-OverStudy to Compare the Relative Efficacy of CAPTISOL-ENABLEDBudesonide+Azelastine Nasal Spray (Single Solution) and RHINOCORTAQUA+ASTELIN Nasal Spray (Two Separate Solutions) against Placebo NasalSpray Solution in the Treatment of Allergic Rhinitis in an EnvironmentalExposure Chamber (EEC) Model

All study drugs were administered as one spray in each nostril. The testtreatment (CAPTISOL-ENABLED Budesonide+Azelastine Nasal Solution) wereadministered along with a placebo in a blinded fashion ensuring that theCAPTISOL-ENABLED formulation is administered first. The referencetreatment (RHINOCORT AQUA Nasal Spray+ASTELIN Nasal Spray) wereadministered in a blinded fashion ensuring that the ASTELIN Nasal Sprayformulation is administered first. Two bottles were used for Treatment C(the placebo treatment). All study medications were administeredintranasally using metered-dose nasal spray pumps. In this particularstudy, the allergic symptoms were due to allergic rhinitis andrhinoconjunctivitis. The test treatment delivered a single spray of 32μg/spray of budesonide and 137 μg/spray of azelastine in each nostril.The reference treatment delivered separate single sprays of 32 μg/sprayof budesonide and 137 μg/spray of azelastine in each nostril. Theplacebo was a single spray in each nostril.

Subjects enrolled in the study (108) were exposed to ragweed pollenusing an EEC model. The nasal symptoms, non-nasal symptoms, and qualityof life for each subject were determined.

After passing the initial Screening Visit (Visit 1), which occurredwithin 30 days prior to randomization (Visit 3), patients attended two3-hour Priming Visits (Visits 2a and 2b) in the EEC. During the PrimingVisits, patients were exposed to ragweed pollen at an average sessionconcentration of approximately 3500±500 particles per m³ for a totalduration of approximately 3 hours. Following an initial 30-minuteexposure, patients were asked to record their instantaneous nasalsymptom scores (NSS) and non-nasal symptom scores (NNSS) every 30minutes for 2.5 hours. Patients were required to meet a minimumthreshold response on one Priming Visit to be eligible to be randomizedon Treatment Day 1 (Visit 3). The minimum threshold is a TNSS of 6units, including a score of at least 2 for congestion on at least onediary card on at least one priming visit.

Patients were not permitted to use rescue medications throughout thestudy. Use of rescue medications would result in removal from the studyat the discretion of the investigator. Patients were monitored foradverse events throughout the exposure sessions.

On Treatment Day 1 (Visit 3), patients reported to the clinicapproximately 1 hour prior to entry into the EEC. The patients werequestioned regarding changes in their health and concomitantmedications. All patients entered the EEC within an approximate10-minute window and were exposed to ragweed pollen in the EEC for aperiod of 12 hours.

Over the first 1.5 hours in the EEC, the patients evaluated their nasaland non-nasal symptoms every 30 minutes to determine adequate baselinesymptoms. Patients who met the predetermined minimum TNSS of 6 units,including a minimum score of 2 for congestion on at least one diary cardprior to treatment, were randomized to receive one of three treatmentsin a double-blind manner. Patients who did not meet the predeterminedTNSS were not dosed and were withdrawn from the study.

Following administration of the study drug, patients were asked toassess their nasal and ocular symptoms (TSS, TNSS and TOSS) at 10, 20,40, 60, 90 and 120 minutes post dose, then every hour up to 10 hourspost-dose. During the entire time (a total of about 12 hours) patientswere in the EEC, they were exposed to ragweed pollen controlled at anaverage session concentration of approximately 3500±500 particles perm³. An EEC-RQLQ was administered prior to entering the EEC, at −0.75hours pre-dose, and post-dose at 2, 6 and 10 hours. At the end of thesession, patients were asked to globally assess the study drug efficacycompared to how they felt prior to its administration (using a 7-pointscale).

Patients were asked to return to the EEC for two priming visits prior toeach of Treatment Days 2 and 3. However, patients were not required toachieve a minimum threshold response on these follow-up priming visits(Visits 4a and 4b and Visits 6a and 6b).

The procedures for Treatment Days 2 and 3 (Visits 5 and 7) was the sameas for Treatment Day 1 described above, except that patients did notneed to meet the predetermined minimum TNSS to proceed in the study.There was a washout period of at least 10 days between treatmentperiods.

The total duration of a patient's participation in this study did notexceed 75 days.

The primary objective of this study was to evaluate the relativeefficacy of CAPTISOL-ENABLED Budesonide+Azelastine Nasal Spray Solutionand RHINOCORT AQUA+ASTELIN Nasal Spray compared to Placebo using TotalNasal Symptom Score (TNSS) in patients with SAR exposed to controlledragweed pollen using an EEC model.

The secondary objectives were to evaluate the relative efficacy of:

-   -   CAPTISOL-ENABLED Budesonide+Azelastine Nasal Spray (Single        Solution) and Budesonide+Azelastine Nasal Spray (Two Separate        Solutions) compared to Placebo by evaluating Total Symptom Score        (TSS) and Total Ocular Symptom Score (TOSS)    -   The three study treatments on an EEC-Rhinoconjunctivitis Quality        of Life Questionnaire (EEC-RQLQ).    -   The three study treatments on the global rating score.

The questions included in the Rhinoconjunctivitis Quality of LifeQuestionnaire for use in the Environmental Exposure Chamber (RQLQ-EEC)were developed using focus groups and were used in the current study asa secondary efficacy measurement. Patients were asked to complete theRQLQ-EEC 5 times at each treatment visit, once before entering the EEC,3 times while in the EEC, and once following the completion of the finalSymptom Diary Card in the EEC. The RQLQ-EEC was administered beforeentering the EEC and during the EEC was divided into 3 domains:non-nose/eye symptoms (10 questions), practical problems (2 questions),and emotions (3 questions). The non-nose/eye symptoms and practicalproblems domains were scored between 0 (not troubled) and 6 (extremelytroubled), and the emotions domain were scored between 0 (none of thetime) and 6 (all of the time). The mean score of the 3 domains yieldedan overall quality-of-life score. The RQLQ-EEC administered at the endof the EEC session consisted of the 3 domains and an additional globalassessment domain. The global assessment was scored between 0 (very muchbetter) and 6 (very much worse).

Patients rated nasal symptoms (rhinorrhea, nasal congestion, nasalitchiness, and sneezing) and non-nasal symptoms (itchy/gritty eyes,tearing/watery eyes, red/burning eyes, itchy ears and palate).

The severity of the nasal and non-nasal symptoms of allergic rhinitiswas recorded on a diary card using the severity rating scale shownbelow. The nasal and non-nasal symptoms are as follows: 1) nasal: runnynose (anterior rhinorrhea/postnasal drainage), itchy nose, nasalcongestion (stuffy nose) and sneezing; 2) non-nasal: itchy/gritty eyes,red/burning eyes, tearing/watery eyes, itchy ear/palate; and 3) ocular:itchy/gritty eyes, red/burning eyes, tearing/watery eyes.

Severity Rating Scale for Allergy Symptoms

Score Definition 0 = none Symptom is not present 1 = mild Sign/symptomis clearly present but minimal awareness; easily tolerated 2 = moderateDefinite awareness of sign/symptom that is bothersome but tolerable 3 =severe Sign/symptom is hard to tolerate; causes interference withactivities of daily living and/or sleep

The TNSS, TOSS and TSS scores were then totaled. The data are set forthin FIGS. 12A-12C.

For every symptom except watery eyes, the AUC of CAPTISOL-ENABLEDBudesonide+Azelastine HCl showed a rank order greater improvement thanthe reference treatment (see FIG. 12I).

The data demonstrate that the composition of the invention is at leastas good as (provides at least the same overall relief of nasal, ocularand total symptoms as does the) combined sequential administration ofthe two commercial products RA and AST.

The data demonstrated the following trends as regards the performance ofthe CAPTISOL ENABLED Budesonide nasal solution (the combinationsolution, “CDX-313”) compared to placebo and the separate and sequentialadministration of RHINOCORT AQUA and ASTELIN:

Total symptom scores: Better than placebo Combination at least as goodas drugs administered separately Total nasal symptom scores Better thanplacebo Combination at least as good as drugs administered separatelyTotal ocular symptom Better than placebo scores Combination comparableto drugs administered separately Duration of action Longer duration ofaction than placebo for relief of nasal symptoms Longer duration ofaction than drugs administered separately for relief of nasal symptoms

A meta analysis was conducted to compare the clinical studies ofExamples 33 (2007) and 34 (2008). Statistical analyses were firstperformed to ensure that the placebo arms between studies behavedsimilarly. An analysis of covariance (ANCOVA) was then performed onbaseline adjusted Area under the Curve (AUC) for TNSS and overall meanchange from baseline in TNSS (placebo arms were pooled). The modelincluded fixed terms for sequence, period and treatment and a randomeffect for subject nested within sequence. Baseline TNSS was used as acovariate in the model after verifying homogeneity of slopes. Allcomparisons were adjusted for multiple testing.

Meta analyses revealed no significant difference in the placebo effectand that placebo effects were comparable (p=0.64) in the two studies,thus allowing pooling of data and comparisons to be made between testproducts with CE and the comparators for both studies. Baseline adjustedAUC and overall mean change from baseline in TNSS showed similar trendsfor both studies (FIGS. 12A and 12I). Change from baseline in AUC forTNSS revealed that when CE-BUD was compared to CE-BUD+AZ there was asignificantly greater relief of nasal symptoms with the combinationproduct than CE-BUD alone (p=0.005) and when RA was compared withCE-BUD−AZ there was a significantly greater relief of nasal symptomswith the combination product than with RA alone (p=0.009) (FIGS. 12K and12L). RA was compared to AS+RA and there was no statisticallysignificant difference after adjustment for multiple testing (p=0.085)and this was also true when CE-BUD was compared with RA (p=0.999). Acomparison of CE-BUD+AZ with AS+RA indicated no statisticallysignificant difference in nasal relief with the solubilized productcompared with each product given individually and consecutively.However, TNSS was numerically lower for CE-BUD+AZ.

In FIGS. 12D and 12E, NSS of runny nose and congestion showed similaronset and duration of action as TNSS. In FIGS. 12F and 12G, onset ofaction of itchy nose and sneezing were significantly faster at 10 minsfor CAPTISOL-ENABLED Budesonide+Azelastine compared to RHINOCORT AQUA.RHINOCORT AQUA/ASTELIN did not show an effect until 0.33 hour. As withthe other parameters, both treatments had the same duration (10 hours)for itchy nose and sneezing.

The CAPTISOL-ENABLED Budesonide+Azelastine formulation provideslong-lasting relief of all allergic rhinitis symptoms similar toconsecutive administration of RHINOCORT AQUA and ASTELIN. However,faster immediate relief of itchy nose and sneezing was obtained in amore convenient combination dose format.

As shown in FIG. 12H, CAPTISOL-ENABLED Budensonide+Azelastine providedthe same or greater numerical TOSS relief (did not reach statisticaldifference) than RHINOCORT AQUA+ASTELIN for 11 of 14 time points andlonger-lasting relief of red/burning eyes (7 h vs. 6 h).

Thus, CAPTISOL-ENABLED Budesonide+Azelastine provided significantlong-lasting relief of all ocular symptoms. It also provided a longerduration of action for the red/burning eyes symptom compared to theRHINOCORT AQUA+ASTELIN format. Additionally, CAPTISOL-ENABLEDBudesonide+Azelastine is provided in a more convenient combinationsingle spray/dose format.

The mean AUC for TSS was significant for CAPTISOL-ENABLEDBudesonide+Azelastine HCl (−45.2±45.02) vs. placebo (−13.3±35.88)(p<0.0001) but was not significantly different from the referencetreatment (−37.3±47.69). The onset of action (defined as the first timepoint after initiation of treatment when the drug demonstrated astatistically significant greater change from baseline in the efficacyendpoint compared to placebo that proved durable from that point onwardfor at least three consecutive time points) of both CAPTISOL-ENABLEDBudesonide+Azelastine HCl and the reference treatment was 0.33 hours. Atevery time point from 0.33 hours onward, both active treatments weresignificantly different from placebo. The reference treatment and testtreatment were never significantly different from each other althoughthe test treatment was numerically superior from 0.33 hours onward. Theduration of action for each active treatment was 10 hours. The TSSmaximum mean decrease from baseline was statistically significant foreach of the active treatments vs. placebo (both p values <0.0001). Themean maximum change was −8.8±5.51 for CAPTISOL-ENABLEDBudesonide+Azelastine HCl, −7.9±5.45 for RHINOCORT AQUA+ASTELIN, and−5.2±4.55 for placebo.

For the non-nasal symptom of itchy ear/palate, CAPTISOL-ENABLEDBudesonide+Azelastine had an onset of action at the 0.33 hr time pointwhile RHINOCORT AQUA+ASTELIN showed efficacy beginning at the 0.66 hrtime point. For this symptom, both treatments maintained efficacy to the10 hr time point. When compared to each other, no significant differencewas observed between the two active treatments for itchy ear/palate atany time point.

For the Overall RQLQ, which groups all of the RQLQ domains together, asignificant treatment effect was observed for CAPTISOL-ENABLEDBudesonide+Azelastine at each of the 2, 6 and 10 hr time points. Thistreatment effect was not observed for RHINOCORT AQUA+ASTELIN at any timepoint. This difference between the two active treatments was alsoevident when comparing the two active treatments to each other at the 6and 10 hr time points. This confirms a significant difference betweenthe two active treatments with CAPTISOL-ENABLED Budesonide+Azelastineshowing efficacy while RHINOCORT AQUA+ASTELIN did not.

CAPTISOL-ENABLED Budesonide+Azelastine HCl was demonstrated to have arapid and durable onset of action against the nasal and ocular symptomsof ragweed allergy. The CAPTISOL-ENABLED Budesonide formulation provideda more convenient combination of a single spray/dose format thansequential RHINOCORT AQUA+ASTELIN. The single spray format offerspotential advantages, such as consistent ratio of actives in every dropof the spray, increased uniformity of dosing, elimination of need tore-suspend drug before use, and ease of manufacture including asepticfiltration to allow the use of valves designed for preservative-freeformulations.

Example 35

Performance of an aqueous liquid composition of the invention in amulti-dose pump nasal spray was evaluated to determine the spray contentuniformity (SCU), pump delivery, spray pattern, droplet sizedistribution. The spray content of a delivered dose or emitted dose isthe quantity of drug outside of the device that is available to asubject on a unit dose basis, i.e. after a single actuation of the pumpnasal spray.

The composition comprised a corticosteroid and antihistamine, e.g.,combination of budesonide (425 μg/mL), azelastine HCl (0.2%), CAPTISOL(10%). The pump nasal spray was adapted to provide a target pumpdelivery (the weight of composition emitted by the device) of 70 mg ofcomposition upon each actuation.

Results from evaluation of performance of an aqueous liquid composition(budesonide (425 μg/mL), azelastine HCl (0.2%), CAPTISOL (10%) inbuffer) in a pump nasal spray.

Droplet Distribution Data:

Dv10 (μm) Dv50 (μm) Dv90 (μm) Span <10 μm (%) 16.73 ± 0.28 32.78 ± 0.1467.48 ± 0.31 1.55 ± 0.03 2.66 ± 0.13 17.11 ± 0.82 33.45 ± 1.63 69.55 ±5.82 1.57 ± 0.07 2.47 ± 0.36 19.68 ± 0.05 39.18 ± 0.88 88.33 ± 2.04 1.75± 0.01 1.68 ± 0.08 19.30 ± 0.17 38.10 ± 0.34 88.36 ± 1.54 1.81 ± 0.04 1.9 ± 0.05 17.31 ± 0.5  36.74 ± 0.63 80.74 ± 3.26 1.73 ± 0.08 2.51 ±0.21 17.39 ± 0.43 35.95 ± 1.25 77.57 ± 4.88 1.67 ± 0.08 2.48 ± 0.2117.33 ± 0.31 35.74 ± 2.52 76.99 ± 8.21 1.66 ± 0.12  2.5 ± 0.21

Spray Pattern Data:

Unit # Dmin (mm) Dmax (mm) Ovality Ratio 3 cm Distance to the Laser BeamSP3-COMBO1 20.0 24.5 1.225 SP3-COMBO2 23.3 33.0 1.416 SP3-COMBO3 24.729.9 1.211 Mean 22.7 29.1 1.284 SD 2.41 4.30 0.11 % CV 10.65 14.77 8.926 cm Distance to the Laser Beam SP6-COMBO1 32.8 57.3 1.747 SP6-COMBO236.8 60.1 1.634 SP6-COMBO3 33.4 47.7 1.428 Mean 34.3 55.0 1.603 SD 2.166.50 0.16 % CV 6.28 11.82 10.09 3 cm Distance to 6 cm Distance to LaserBeam Laser Beam Spray Weight Spray Weight Unit # (mg) Unit # (mg)SP3-COMBO1 55.5 SP6-COMBO1 71.7 SP3-COMBO2 73.0 SP6-COMBO2 75.1SP3-COMBO3 70.4 SP6-COMBO3 70.8 Mean 66.3 Mean 72.5 SD 9.44 SD 2.27 % CV14.24 % CV 3.13 Unit # Spray Weight (mg) COMBO1-DSD3 69.6 COMBO2-DSD372.8 COMBO3-DSD3 68.0 Mean 70.1 SD 2.44 % CV 3.48

The results indicate that the mean pump delivery ranged from 72.5 to74.5 mg per actuation with a standard deviation ranging from ±0.54 to±1.6. The plume emitted by the nasal spray was characterized by laserdiffraction to determine the droplet size distribution (Dv10, Dv50,Dv90), span and percentage of droplets having a droplet size of <10 μm.The mean Dv10 ranged from 16.73 to 19.68 μm with a standard deviationranging from ±0.05 to ±0.82 μm. The mean Dv50 ranged from 32.78 to 39.18μm with a standard deviation ranging from ±0.14 to ±1.63 μm. The meanDv90 ranged from 67.48 to 88.36 μm with a standard deviation rangingfrom ±0.31 to ±5.82 μm. The mean span ranged from 1.55 to 1.81 with astandard deviation ranging from ±0.01 to ±0.08 μm. The percentage ofdroplets <10 μm in size ranged from 1.68 to 2.66% with a standarddeviation ranging from ±0.05 to ±0.36%.

Example 36

An ophthalmic solution comprising a corticosteroid and SAE-CD isprepared as follows.

Method A. Fluticasone Propionate

A citrate buffer solution at a pH of 4.5 was prepared by mixing variousportions of 0.003M citric acid with 0.003M of trisodium citrate. Aphosphate buffer solution at a pH of 6.0 was prepared by mixing variousportions of 0.003M monobasic sodium phosphate with 0.003M of dibasicsodium phosphate. These stock solutions contained 10% w/v SBE-Gamma(D.S.=6.1) and 0.01% TWEEN. An excess of fluticasone propionate wasadded to the vials and equilibrated on a rocker for three days. Thesamples were then filtered using a PVDF 0.22 μm syringe filter. Aliquotsof the solutions were placed into clear glass 2 mL serum vials withaluminum crimp caps and Dalkyo Fluorotec septums. The concentration ofthe pH 4.5 solution was 232 μg/mL. The concentration of the pH 6.0solution was 238 μg/mL.

Method B. Mometasone Furoate

A 50 mL solution of 0.08M CAPTISOL with 80 μg/mL of mometasone furoatewas prepared by weighing approximately 9.6 grams of CAPTISOL into a 50mL volumetric flask and qs with a 3 mM citrate buffer pH 4.5. Theapproximately 4 mg of mometasone furoate was weighed into a media bottleand the CAPTISOL/buffer solution was added to the drug and the bottleswere vortexed and sonicated for approximately 5 minutes. The bottleswere then placed on a roller mixer (Stuart Scientific SRT2 33 rpmrise/fall 16 mm) protected from light and mixed overnight. After theovernight mixing on the roller mixer the bottles were transferred to amagnetic stirrer, set at 330 RPM, for three days. The solutions werefiltered using a PVDF 0.22 μm filter and a sample was assayed from eachbottle. The results from the assay were about 6% low from target soadditional mometasone furoate anhydrous was added to each bottle andwere placed back onto the roller mixer for another 3 days. The solutionswere aseptically filtered again and 2 mLs were transferred to the 2 mLclear vials with Teflon stoppers.

Method C. Mometasone Furoate and SBE-γ-CD

A 50 mL solution of 0.08M SBE γ-CD with 400 μg/mL of mometasone furoatewas prepared by weighing approximately 9.1 grams of SBE γ-CD into a 50mL volumetric flask and qs with a 3 mM citrate buffer pH 4.5. Theapproximately 20 mg of mometasone furoate was weighed into a mediabottle and the SBE γ-CD/buffer solution was added to the drug and thebottles were vortexed and sonicated for approximately 5 minutes. Thebottles were then placed on a roller mixer (Stuart Scientific SRT2 33rpm rise/fall 16 mm) protected from light and mixed overnight. After theovernight mixing on the roller mixer the bottles were transferred to amagnetic stirrer, set at 330 RPM, for three days. The solutions werefiltered using a PVDF 0.22 μm filter and a sample was assayed from eachbottle. The results from the assay were about 6% low from target soadditional mometasone furoate anhydrous was added to each bottle andwere placed back onto the roller mixer for another 3 days. The solutionswere aseptically filtered again and 2 mLs were transferred to the 2 mLclear vials with Teflon stoppers.

Example 37

Preparation of ophthalmic budesonide solution and its placebo for invivo-testing.

Method A

A buffered, isotonic CAPTISOL solution was prepared. 100 mL water wasplaced in a suitable vessel. Approximately 4.2 grams of CAPTISOL,approximately 32.3 milligrams of citric acid monohydrate, approximately43.3 milligrams of sodium citrate dihydrate, and approximately 580milligrams of sodium chloride were added to the vessel. The solution wasmixed with a magnetic stir-bar until all solids were dissolved. Themeasured pH was 4.5 and the tonicity was 300mOs.

Method B

The same procedure was followed as was in Method A, with the addition ofbudesonide and polysorbate-80 after the CAPTISOL, citric acidmonohydrate, sodium citrate dihydrate, and sodium chloride weredissolved. Approximately 26.2 milligrams of budesonide was added to thevessel and allowed to mix for approximately 2.5 hours. Approximately 5.0microliters of polysorbate-80 was added to the vessel and allowed to mixfor an additional approximately 2.5 hours. This solution was filtered toremove undissolved excess budesonide, then assayed by HPLC to determinethe final budesonide concentration, which was 251 micrograms permilliliter. The measured pH was 4.5 and the tonicity was 300 mOs.

Example 38

Preparation and use of a combination solution containing SAE-CD,budesonide, and azelastine. A solution can be made according to Example37, except that 500 mg of azelastine is added to the vessel with thebudesonide.

Example 39

Preparation and use of a combination solution containing SAE-CD,budesonide, and diclofenac.

A citrate buffer (3 mM pH 4.5) is prepared as follows. Approximately62.5 mg of citric acid is dissolved in and brought to volume with waterin one 100 mL volumetric flask. Approximately 87.7 mg of sodium citrateis dissolved in and brought to volume with water in another 100 mLvolumetric flask. In a beaker the sodium citrate solution is added tothe citric acid solution until the pH is approximately 4.5.

Approximately 10.4 mg of budesonide, 100 mg of diclofenac and 1247.4 mgof CAPTISOL are ground together with a mortar and pestle and transferredto a 10 mL flask. Buffer solution is added, and the mixture is vortexed,sonicated and an additional 1.4 mg budesonide added. After shakingovernight, the solution is filtered through a 0.22 μm Durapore Millex-GVMillipore syringe filter unit. The resulting budesonide concentrationwill be approximately 1 mg/mL and the concentration of diclofenac willbe approximately 10 mg/mL.

Example 40

Preparation and use of a combination ophthalmic solution comprisingCAPTISOL, ofloxacin, and mometasone furoate.

A 50 mL solution of 0.08M CAPTISOL with 80 μg/mL of mometasone furoateand 3 mg/mL ofloxacin can be prepared by weighing approximately 9.6grams of CAPTISOL into a 50 mL volumetric flask and qs with a 3 mMcitrate buffer pH 4.5. The approximately 4 mg of mometasone furoate and150 mg ofloxacin are weighed into a media bottle and the CAPTISOL/buffersolution was added to the drug and the bottles vortexed and sonicatedfor approximately 5 minutes. The bottles are then placed on a rollermixer (Stuart Scientific SRT2 33 rpm rise/fall 16 mm) protected fromlight and mixed overnight. After the overnight mixing on the rollermixer the bottles are transferred to a magnetic stirrer, set at 330 RPM,for three days. The solutions are filtered using a PVDF 0.22 μm filterand a sample assayed from each bottle.

Example 41

In vivo evaluation of a dosage form according to the invention wasconducted in rabbits as follows.

A pilot study to test the effectiveness of CE-Budesonide on ocular woundhealing was conducted in rabbits. The effectiveness of CE-Budesonide(250 mcg/mL) from Example 37 was compared with commercialproducts—PULMICORT RESPULES (a suspension of budesonide, 250 mcg/mL) andprednisolone acetate (Pred Forte suspension, 1%) and a CAPTISOL placebo.

Treatment Protocol:

The animals were administered 40 microliter (10 μg) of test materialeach to both eyes of animals four times a day (6 hours apart) for 3 daysprior to induction of eye injury by laser energy on Day 0 (the day ofinduction of eye injury). Each animal was placed in the left lateralposition and thermal injury was made to the right eye with asemiconductor, diode laser. Laser energy was directed through theperipheral clear cornea to the iris surface using a hand-held fiberopticlaser probe injuring three separate sites measuring 2 mm in diameter.Laser energy treatment of the eyes resulted in inflammatory responses ofthe iris along with proteinaceous and cellular inflammation in theanterior chamber of the eye on Day 0. The injury was graded forinflammation based on the study Ophthalmologist's routine criteria (0:no inflammation, 1: trace flare or cells (very faint), 2: flare/cellmild but clearly visible in anterior chamber, 3: flare/cell turbitymoderate in anterior chamber, 4: flare/cell severe in anterior chamber).Ocular pressure was determined using an applanation tonometer.

Anterior Anterior chamber chamber Number Of Eye drop flare¹ cell¹Animals volume score Score Group Treatment Concentration M microliter D0D1 D0 D1² 1 Vehicle Control  0 mcg/mL 4 40 1.75 1 1.25 0 (~4% CAPTISOL)2 PUMICORT RESPULES 250 mcg/mL 4 40 1.75 1 1.25 0.25 (a suspension ofbudesonide) 3 prednisolone 1% 4 40 1.75 0.75 1.25 0.25 acetate (PredForte suspension) 4 CAPTISOL- 250 mcg/mL 4 40 2 0 1.25 0 ENABLEDBudesonide ¹Average score of 4 animals. Day 0: the day injury wasinduced. ²Group 2 and 3 each had one animal scored as 1+, all otherswere 0.

Slit lamp examinations revealed aqueous flare, conjunctivitis, iritis,and/or superficial keratitis of the right eye following the laser injuryin all animals. Aqueous flare had resolved by Day 3 in all animals butone in the PULMICORT RESPULES group.

Decreased eye pressure in the right eye was observed in all animalsfollowing laser injury on Day 0. Eye pressure returned to normal valuesin the CAPTISOL-ENABLED Budesonide solution group by Day 1, and inCAPTISOL vehicle controls, PULMICORT RESPULES, and PRED FORTE by Day 3,7, and 3, respectively. The results are summarized in the table belowand in FIGS. 9 a and 9 b.

Eye Pressure (Mean ± SD) CAPTISOL- Surgical PULMICORT ENABLED dayCAPTISOL RESPULES Pred Forte Budesonide Left Eye D-1 17.00 ± 2.71 20.00± 1.83 21.25 ± 0.96 17.25 ± 5.12 D0 19.25 ± 2.22 18.75 ± 2.22 19.25 ±1.50 19.50 ± 1.91 D1 21.75 ± 2.50 21.00 ± 3.37 20.75 ± 2.75 19.75 ± 2.50D3 20.75 ± 1.26 18.75 ± 2.22 20.50 ± 2.08 21.75 ± 1.50 D7 19.25 ± 2.5021.25 ± 2.36 20.00 ± 1.41 19.50 ± 1.73 Right Eye D-1 16.75 ± 3.69 18.25± 2.06 20.25 ± 2.22 17.75 ± 4.35 D0 17.00 ± 2.71 20.00 ± 1.83 21.25 ±0.96 17.25 ± 5.12 D1 13.75 ± 5.62 16.00 ± 3.92 13.25 ± 2.50 20.25 ± 0.96D3 15.75 ± 3.10 11.25 ± 4.43 18.50 ± 3.00 20.75 ± 2.50 D7 21.00 ± 2.1619.75 ± 2.06 18.25 ± 3.40 19.25 ± 1.71

The results showed that CE-Budesonide solution effectively reducedinflammatory reactions following laser injury to the iris of rabbits.The resolution of laser-induced eye injury by CAPTISOL-ENABLEDBudesonide occurs more rapidly than by either PULMICORT RESPULES, orPRED FORTE. Intraocular pressure returned to normal values more quicklyin the CE-Budesonide solution treatment group than in all othertreatment groups and the vehicle control.

Example 42

Preparation and use of a combination ophthalmic solution containingSAE-CD, budesonide and tobramycin.

An ophthalmic solution of the invention can be made to contain thefollowing ingredients in the approximate amounts indicated per mL ofsolution.

Ingredient Amount in 1 mL of solution Tobramycin  0.3% (3 mg) Budesonide0.025% (250 μg) Benzalkonium chloride 0.01% SBE-γ-CD   2% Edentatedisodium  0.1% Sodium chloride 0.01% Sulfuric acid and/or sodium Toadjust pH to physiologic pH hydroxide Water Qs. to 1 mL

Example 43

Preparation and use of a combination ophthalmic solution containingSAE-CD, budesonide and azithromycin.

Ingredient Amount in 1 mL of solution Azithromycin  0.5% (5 mg)Budesonide 0.025% (250 μg) Benzalkonium chloride 0.01% SBE-γ-CD   2%Edentate disodium  0.1% Sodium chloride 0.01% Sodium sulfate, sulfuricacid To adjust pH to physiologic pH and/or sodium hydroxide Water Qs. to1 mL

Example 44

Preparation of ophthalmic solution of SBE γ-CD, Mometasone Furoate, andTimolol

A 50 mL solution of 0.08M SBE γ-CD with 400 μg/mL of mometasone furoateand 2.5 mg/mL of timolol can be prepared by weighing approximately 9.1grams of SBE γ-CD into a 50 mL volumetric flask and qs with a 3 mMcitrate buffer pH 4.5. The approximately 20 mg of mometasone furoate and125 mg of timolol are weighed into a media bottle and the SBEγ-CD/buffer solution is added to the drugs. The bottles are vortexed andsonicated for approximately 5 minutes. The bottles are then placed on aroller mixer (Stuart Scientific SRT2 33 rpm rise/fall 16 mm) protectedfrom light and mixed overnight. After the overnight mixing on the rollermixer the bottles are transferred to a magnetic stirrer, set at 330 RPM,for three days. The solutions are filtered using a PVDF 0.22 μm filter.

Example 45

The table below summarizes some solubility data for the listedcorticosteroids in the absence (intrinsic solubility of corticosteroidin the aqueous test medium) and in the presence of two differentSAE-CD's as determined herein.

[Steroid] ×10⁵ M Intrinsic Solubility 0.04 M 0.04 M Steroid ID (H₂O)CAPTISOL (SBE)_(6.1) γ Hydrocortisone 92.4 2656.3 2369.3Methylprednisolone 43.6 743.1 1215.3 Prednisolone 62.5 1995.3 2095Prednisone 50.5 1832.7 1313.7 Flunisolide 11.3 261.5 455.1Beclomethasone 0.41 11.6 46.8 Dipropionate Budesonide 6.6 254.8 306.6Fluticasone Propionate 0.39 5.41 51.8 Mometasone Fuorate 1.82 16.4 41.5Triamcinolone Acetonide 3.56 457 1059.5

Example 46

The table below summarizes the equilibrium binding constants (K) forsome corticosteroids in the presence of CAPTISOL or SBE6. 1-γ-CD (0.04M).

Binding Constant-K Steroid ID CAPTISOL (SBE)_(6.1) γ Hydrocortisone 19321430 Methylprednisolone 486 950 Prednisolone 1496 1653 Prednisone 1591914 Flunisolide 590 1104 Beclomethasone 684 2862 Dipropionate Budesonide1002 1229 Fluticasone Propionate 322 3338 Mometasone Fuorate 201 551Triamcinolone Acetonide 3591 10075

Example 47

An aqueous budesonide/olopatadine solution was prepared. The targetcomposition was budesonide 320 μg/mL, olopatadine HCl 6.6 mg/mL, andCAPTISOL 5, 7.5 and 10% w/v.

Part A

Three mM citrate buffer was prepared at pH 4.5. Approximately 0.32 gramsof citric acid monohydrate and approximately 0.44 grams of sodiumcitrate dihydrate were dissolved with water in 500 mL volumetric flasks,respectively. Those citrate solutions were mixed to adjust the pH to4.5. Three CAPTISOL solutions (5, 7.5 and 10% w/v) were prepared withthe 3 mM citrate buffer at pH 4.5. Approximately 5.2, 7.9 and 10.5 gramsof CAPTISOL were dissolved with 3 mM citrate buffer at pH 4.5 in 100 mLvolumetric flasks, respectively. The solutions were transferred into 250mL amber beakers with a magnetic stir disk. The solutions were mixedwith a magnetic stir disk at 900 rpm at a temperature of 35° C.

Approximately 34 milligrams of budesonide was suspended in each CAPTISOLsolution. The samples were mixed with a magnetic stir disk at 900 rpmand 35° C. After 24 hours, the samples were filtered through 0.22 μmPVDF filter. The budesonide in the aliquots was assayed by an HPLC assaymethod and the concentrations were ˜340 μg/mL. The measured pHs were˜4.4 and the tonicities with CAPTISOL 5, 7.5 and 10% w/v were 132, 202and 277 mOsm, respectively.

Part B

Approximately 27 milligrams of olopatadine HCl was weighed into each ofthree 2 drams amber vials. The olopatadine HCl was suspended to 4 mL ofbudesonide/CAPTISOL solutions prepared in Part A. The samples were mixedon a roller mixer at RT. After 24 hours, the samples were filteredthrough 0.22 μm PVDF filter. The olopatadine and budesonide in thealiquots was assayed by HPLC assay methods, respectively. Allolopatadine HCl concentrations were >6.6 mg/mL and all budesonideconcentrations were >320 μg/mL. The ratio of budesonide epimer B tobudesonide epimer A (R/S ratio) of budesonide solution with 5% w/vCAPTISOL was 1.09 and it was decreased to 1.07 after olopatadinedissolved. The R/S ratios of other samples were 1.09. The measured pHswere ˜3.8 and the tonicities with CAPTISOL 5, 7.5 and 10% w/v were 154,224 and 297 mOsm, respectively.

Part C

Approximately 27 milligrams of olopatadine HCl were weighed into each ofthree 2 drams amber vials. The olopatadine HCl was suspended to 4 mL ofbudesonide/CAPTISOL solutions prepared in Part A. The samples were mixedon a roller mixer at RT. After 1 hour, the pH of each sample wasadjusted to 4.5 with 1N NaOH. Again, the samples were mixed on a rollermixer at RT. After 23 hours, a precipitation was observed in thepresence of 5% w/v CAPTISOL at pH 4.5. All samples were filtered through0.22 μm PVDF filter. The olopatadine and budesonide in the aliquots wereassayed by HPLC assay methods, respectively. The olopatadine HClconcentrations with CAPTISOL 7.5 and 10% w/v were >6.6 mg/mL, but theconcentration with CAPTISOL 5% w/v was 6.5 mg/mL. The budesonideconcentrations with CAPTISOL 7.5 and 10% w/v were >320 μg/mL, but theconcentration with CAPTISOL 5% w/v was 210 μg/mL. The R/S ratio ofbudesonide solution with 5% w/v CAPTISOL from Part A was 1.09 and it wasdecreased to 0.6 after olopatadine dissolved. The R/S ratios of othersamples were 1.09. The measured pHs were ˜4.5 and the tonicities withCAPTISOL 5, 7.5 and 10% w/v were 159, 228 and 301 mOsm, respectively.

All documents cited herein are each incorporated by reference herein inits entirety. The above is a detailed description of particularembodiments of the invention. It will be appreciated that, althoughspecific embodiments of the invention have been described herein forpurposes of illustration, various modifications may be made withoutdeparting from the spirit and scope of the invention. Accordingly, theinvention is not limited except as by the appended claims.

1. A method for treating an allergic symptom or disorder in a subject inneed thereof, comprising: nasally administering to the subject acorticosteroid solution comprising a therapeutically effective amount ofa corticosteroid, SAE-CD, and a pharmaceutically acceptable aqueousliquid carrier, wherein the allergic symptom or disorder includes anon-nasal symptom selected from the group consisting of itchy/grittyeyes, tearing/watery eyes, red/burning eyes, itchy ears/palate andcombinations thereof.
 2. The method of claim 1, wherein the allergicsymptom or disorder further comprises symptoms selected from the groupconsisting of runny nose, itchy nose, nasal congestion, sneezing andcombinations thereof.
 3. The method of claim 1, wherein saidcorticosteroid solution further comprises a therapeutically effectiveamount of an antihistamine.
 4. The method of claim 3, wherein theantihistamine is azelastine, olopatadine pharmaceutically acceptablesalts thereof, pharmaceutically active metabolites thereof, opticallyactive isomers or racemates, and mixtures thereof; the corticosteroid isbudesonide; and the SAE-CD is CAPTISOL cyclodextrin (sulfobutyletherβ-cyclodextrin).
 5. The method of claim 4, wherein the azelastine ispresent in an amount of about 30 μg to about 275 μg per unit dose, orthe olopatadine is present in an amount of about 150 μg to about 1400 μgper unit dose, the budesonide is present in an amount of about 5 μg toabout 500 μg per unit dose, and the CAPTISOL is present in an amount of100 μg to 100 mg per unit dose.
 6. The method of claim 1, wherein thecorticosteroid solution is administered 1-2 times per day.
 7. A methodfor treating an ocular symptom or disorder in a subject in need thereof,comprising: nasally administering to the subject a corticosteroidsolution comprising a therapeutically effective amount of acorticosteroid, SAE-CD, and a pharmaceutically acceptable aqueous liquidcarrier, wherein the allergic symptom or disorder includes a non-nasalsymptom selected from the group consisting of itchy/gritty eyes,tearing/watery eyes, red/burning eyes, itchy ears/palate andcombinations thereof.
 8. The method of claim 7, wherein saidcorticosteroid solution further comprises a therapeutically effectiveamount of an antihistamine.
 9. The method of claim 8, wherein theantihistamine is azelastine, olopatadine, pharmaceutically acceptablesalts thereof, pharmaceutically active metabolites thereof, opticallyactive isomers or racemates, and mixtures thereof; the corticosteroid isbudesonide; and the SAE-CD is CAPTISOL cyclodextrin (sulfobutyletherβ-cyclodextrin).
 10. The method of claim 9, wherein the azelastine ispresent in an amount of about 30 μg to about 275 μg per unit dose or theolopatadine is present in an amount of about 150 μg to about 1400 μg perunit dose, the budesonide is present in an amount of about 5 μg to about500 μg per unit dose, and the CAPTISOL is present in an amount of 100 μgto 100 mg per unit dose.
 11. The method of claim 7, wherein thecorticosteroid solution is administered 1-2 times per day.
 12. A methodfor treating ocular inflammation in a subject in need thereof,comprising: ophthalmically administering to the subject a corticosteroidsolution comprising a therapeutically effective amount of acorticosteroid, SAE-CD, and a pharmaceutically acceptable aqueous liquidcarrier, wherein the corticosteroid solution provides more rapidreduction in ocular inflammation compared with a corticosteroidsuspension at the same unit dose.
 13. The method of claim 12, whereinsaid corticosteroid solution further comprises a therapeuticallyeffective amount of an antihistamine.
 14. The method of claim 13,wherein the antihistamine is azelastine, olopatadine, pharmaceuticallyacceptable salts thereof, pharmaceutically active metabolites thereof,optically active isomers or racemates, and mixtures thereof; thecorticosteroid is budesonide; and the SAE-CD is CAPTISOL cyclodextrin(sulfobutylether β-cyclodextrin).
 15. The method of claim 14, whereinthe azelastine is present in an amount of about 30 μg to about 275 μgper unit dose or the olopatadine is present in an amount of about 150 μgto about 1400 μg per unit dose, the budesonide is present in an amountof about 5 μg to about 500 μg per unit dose, and the CAPTISOL is presentin an amount of 100 μg to 100 mg per unit dose.
 16. The method of claim12, wherein the corticosteroid solution is administered 1-2 times perday.
 17. A metered dose device for nasal or ophthalmic administrationcomprising: corticosteroid solution comprising a therapeuticallyeffective amount of corticosteroid, a therapeutically effective amountof an antihistamine, SAE-CD, and a pharmaceutically acceptable aqueousliquid carrier.
 18. The device of claim 17, wherein the antihistamine isazelastine, olopatadine, pharmaceutically acceptable salts thereof,pharmaceutically active metabolites thereof, optically active isomers orracemates, and mixtures thereof; the corticosteroid is budesonide; andthe SAE-CD is CAPTISOL cyclodextrin (sulfobutylether β-cyclodextrin).19. The device of claim 18, wherein the azelastine is present in anamount of about 30 μg to about 275 μg per unit dose or the olopatadineis present in an amount of about 150 μg to about 1400 μg per unit dose,the budesonide is present in an amount of about 5 μg to about 500 μg perunit dose, and the CAPTISOL is present in an amount of 100 μg to 100 mgper unit dose.
 20. A system for treating an allergic symptom comprising:corticosteroid solution comprising a therapeutically effective amount ofa corticosteroid, a therapeutically effective amount of anantihistamine, SAE-CD and a pharmaceutically acceptable aqueous liquidcarrier, and a metered dose device for nasal or ophthalmicadministration of the corticosteroid solution to the subject.
 21. Thesystem of claim 20, wherein the allergic symptom is selected from thegroup consisting of runny nose, itchy nose, nasal congestion, sneezing,itchy/gritty eyes, red/burning eyes, tearing/watery eyes and itchyears/palate and combinations thereof.
 22. The system of claim 21,wherein the allergic symptom is selected from the group consisting ofitchy/gritty eyes, tearing/watery eyes, red/burning eyes, itchy ears andpalate and combinations thereof.
 23. The system of claim 20, wherein theantihistamine is azelastine, olopatadine, pharmaceutically acceptablesalts thereof, pharmaceutically active metabolites thereof, opticallyactive isomers or racemates, and mixtures thereof; the corticosteroid isbudesonide; and the SAE-CD is CAPTISOL cyclodextrin (sulfobutyletherβ-cyclodextrin).
 24. The system of claim 23 wherein the azelastine ispresent in an amount of about 30 μg to about 275 μg per unit dose or theolopatadine is present in an amount of about 150 μg to about 1400 μg perunit dose, the budesonide is present in an amount of about 5 μg to about500 μg per unit dose, and the CAPTISOL is present in an amount of 100 μgto 100 mg per unit dose.